Integrin expression inhibitor

ABSTRACT

The present invention provides an integrin expression inhibitor, and an agent for treating arterial sclerosis, psoriasis, cancer, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, an anticoagulant, or a cancer metastasis suppressor on the basis of an integrin inhibitory action. Namely, it provides an integrin expression inhibitor comprising, as an active ingredient, a sulfonamide compound represented by the following formula (I), a pharmacologically acceptable salt thereof or a hydrate of them, 
     
       
         
         
             
             
         
       
     
     wherein in the formula, B means a C6-C10 aryl ring or 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated; K means a single bond, —CH═CH— or —(CR 4b R 5b ) m   b — (wherein R 4b  and R 5b  are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group; and m b  means an integer of 1 or 2); R 1  means hydrogen atom or a C1-C6 alkyl group; Z means a single bond or —CO—NH—; and R means a C6-C10 aryl ring or 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated, respectively.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 37 CFR §1.53(b) divisional of U.S. applicationSer. No. 11/097,218 filed Apr. 4, 2005, which is a 37 CFR §1.53(b)continuation of U.S. application Ser. No. 10/181,562 filed on Jul. 18,2002 (now abandoned), which is the national phase under 35 U.S.C. §371of PCT Application No. PCT/JP01/00713, which has an international filingdate of Feb. 1, 2001, which designated the United States of America. PCTApplication No. PCT/JP01/00713 claims priority on Japanese ApplicationNos. 2000-26080 filed Feb. 23, 2000, and 2000-402084 filed Dec. 28,2000. Each of the above-identified applications is hereby incorporatedby reference.

TECHNICAL FIELD

The present invention relates to an integrin expression inhibitor,specifically, an integrin α2β1, α3β1, α5β1, α6β1, αvβ1, αvβ3 or αvβ5expression inhibitor. Further it relates to an angiogenesis agent, ananticoagulant, an anticancer agent, a cancer metastasis suppressor, andan agent for treating retinal angiogenesis, diabetic retinopathy,inflammatory diseases, arterial sclerosis, psoriasis and osteoporosis,on the basis of integrin expression inhibitory action.

PRIOR ART

Integrin structurally consists of a heterodimer in which two types ofsub-unit, namely, integrin α and integrin β are associated with eachother by non-covalent binding. At least 16 types of α chains and 8 typesof β chains have been found. A variety of molecular groups differing inligand specificity are formed by the combination of these α and β chainsand 22 types of integrins have been known. Integrin has a function ascell membrane receptor protein for an adhesive molecule of an animalcell, expresses on a cell membrane and participates in the adhesionbetween a cell and an extracellular matrix (ECM) or between cells. Whenthe cell adhesive molecule is combined with integrin, a signaling systemin a cell starts moving and as a result, not only cell adhesion, butalso cell evolution, cell proliferation, apoptosis, differentiation,cytoskeleton orientation, cell migration, histogenesis, cancerinfiltration and metastasis, wound healing, blood coagulation and thelike operate. It has been known that among these integrins, integrinα2β1 of which the adhesive molecules are collagen and lamininparticipates in platelet aggregation, cancer infiltration and metastasis(HAYASHI Masao & MIYAMOTO Yasunori, PROTEIN, NUCLEIC ACID, ENZYME, Vol.44, pp 130-135, (1999)) and angiogenesis (Donald R. Senger et al, Proc.Natl. Acad. Sci. USA, 94, 13612-13617, (1997)). It has come to beclarified that among these symptoms, the proliferation of cancer isclosely related to angiogenesis. In recent years, it has beendemonstrated experimentally that an antiangiogenesis agent can inhibitand further reduce proliferative cancer and no resistant cancer isgenerated in a transplant cancer model and there is shown a correlationbetween angiogenesis and exacerbations of many solid cancers such asmammary cancer, prostatic cancer, lung cancer and colonic cancer inclinical examinations (T. Boem et al, Nature, 390 (27) 404-407, (1997)).Also, αvβ1 of which the adhesive molecules are fibronectin andvitronectin participates in the adhesion of a cancer cell to a substrateand αvβ3 of which the adhesive molecules are vitronectin andthrombospongin and αvβ5 of which the adhesive molecule is vitronectinparticipate in angiogenesis, cancer metastasis and the regeneration ofbone (Shattil, S. J., Thromb. Haemost., 74, 149-155, (1995), FriedlanderM, et al, Science, 270, 1500-1502, (1995)). Further, it has been knownthat α3β1 of which the adhesive molecules are fibronectin, collagen,laminin, laminin 5 and the like, α5β1 of which the adhesive molecule isfibronectin and α6β1 of which the adhesive molecules are laminin andlaminin 5 participate in cancer infiltration and metastasis (MATSUURANariaki et al., JAPAN CLINIC, Vol. 53, pp 1643-1647, (1995), OTA Ichiroet al, CLINICAL PATHOLOGY, Vol. 45, 528-533, (1997)).

WO9950249 discloses the antagonist of integrin αvβ3, however there is nosuggestion concerning the expression inhibitory action of integrin αvβ3.In JP-A 7-165708 and JP-A 8-231505, the same sulfonamide compound asthat used in the present invention is disclosed; however, there isneither description nor hint concerning integrin expression inhibitoryaction. WO9301182 discloses anti-tumor agents utilizing a specifictyrosine kinase inhibitive action of a compound having an indoleskeleton. These agents are indolylmethylene-2-indolinone compounds,which differ from that of the present invention. WO964016 likewisediscloses anti-tumor agents utilizing a specific tyrosine kinaseinhibitory action of a compound having an indole skeleton. However,these agents are 2-indolinone-3-methylene derivatives, which differ fromthat of the present invention.

An antiangiogenesis agent, an anticancer agent, a cancer metastasissuppressor, an anticoagulant agent, and an agent for treating arterialsclerosis, psoriasis, retinal angiogenesis, diabetic retinopathy orinflammatory diseases on the basis of an integrin expression inhibitoryaction have not been known so far.

The present invention provides an agent for treating a disease againstwhich an integrin expression inhibitory action is effective.Specifically, it is an object of the present invention to provide anantiangiogenic agent, an anticancer agent, a cancer metastasissuppressor, an anticoagulant, and an agent for treating arterialsclerosis, psoriasis, osteoporosis, retinal angiogenesis, diabeticretinopathy or inflammatory diseases, which comprises, as an activeingredient, a compound having an integrin expression inhibitory action.Another object of the present invention is to provide an integrinexpression inhibitor comprising a sulfonamide compound.

DISCLOSURE OF THE INVENTION

The present inventors have made earnest studies and as a result, foundthat a sulfonamide compound having a bicyclic heterocycle has anintegrin expression inhibitory action. Thus, they have completed thepresent invention.

Accordingly, the present invention relates to:

1. 1) an agent for treating arterial sclerosis, psoriasis, cancer,osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatorydiseases, 2) an anticoagulant, 3) a cancer metastasis suppressor or 4)an antiangiogenic agent on the basis of an integrin expressioninhibitory action, 2. 1) the agent for treating arterial sclerosis,psoriasis, cancer, osteoporosis, retinal angiogenesis, diabeticretinopathy or inflammatory diseases, 2) an anticoagulant, 3) a cancermetastasis suppressor or 4) an antiangiogenic agent on the basis ofintegrin expression inhibitory action as described in 1., wherein theintegrin is integrin α2, α3, α5, α6, αv, β1, β3, β4, β5, α2β1, α3β1,α5β1, α6β1, αvβ1, αvβ3 or αvβ5, 3. an integrin expression inhibitorcomprising, as an active ingredient, a sulfonamide compound representedby the formula (I), a pharmacologically acceptable salt thereof or ahydrate of them:

(in the formula, B represents a C6-C10 aryl ring or a 6- to 10-memberedheteroaryl ring which may have a substituent and in which a part of thering may be saturated; K represents a single bond, —CH═CH— or—(CR^(4b)R^(5b))_(m) ^(b)— (where R^(4b) and R^(5b) are the same as ordifferent from each other and each represents hydrogen atom or a C1-C4alkyl group; and m^(b) means an integer of 1 or 2); R¹ representshydrogen atom or a C1-C6 alkyl group; Z represents a single bond or—CO—NH—; and R represents a C6-C10 aryl ring or a 6- to 10-memberedheteroaryl ring which may have a substituent and in which a part of thering may be saturated, respectively), 4. an integrin expressioninhibitor comprising, as an active ingredient, the sulfonamide compoundas described in 3., a pharmacologically acceptable salt thereof or ahydrate of them, wherein R is indole, quinoline or isoquinoline, 5. anintegrin expression inhibitor comprising, as an active ingredient, asulfonamide compound represented by the formula (I^(a)), apharmacologically acceptable salt thereof or a hydrate of them:

(in the formula, the A^(a) ring a monocyclic or bicyclic aromatic ringwhich may have a substituent; the B^(a) ring represents an optionallysubstituted 6-membered cyclic unsaturated hydrocarbon or unsaturated6-membered heterocycle containing one nitrogen atom as a heteroatom; theC^(a) ring represents an optionally substituted 5-membered heterocyclecontaining 1 or 2 nitrogen atoms; R^(1a) represents hydrogen atom or aC1-C6 alkyl group; W^(a) represents a single bond or —CH═CH—; Y^(a)represents carbon atom or nitrogen atom; and Z^(a) represents—N(R^(2a))— (wherein R^(2a) means hydrogen atom or a lower alkyl group)or nitrogen atom, respectively), 6. an integrin expression inhibitorcomprising, as an active ingredient, the sulfonamide compound asdescribed in 5., a pharmacologically acceptable salt thereof or ahydrate of them, wherein W^(a) is a single bond, 7. an integrinexpression inhibitor comprising, as an active ingredient, thesulfonamide compound as described in 5., a pharmacologically acceptablesalt thereof or a hydrate of them, wherein W^(a) is a single bond; Z^(a)is —NH—; and Y^(a) is carbon atom, 8. the integrin expression inhibitorcomprising, as an active ingredient, a the sulfonamide compound asdescribed in any of 5., 6. and 7., a pharmacologically acceptable saltthereof or a hydrate of them, wherein the B^(a) ring is an optionallysubstituted benzene or pyridine, 9. an integrin expression inhibitorcomprising, as an active ingredient, the sulfonamide compound asdescribed in any of 5. to 8., a pharmacologically acceptable saltthereof or a hydrate of them, wherein the C^(a) ring is an optionallysubstituted pyrrole, 10. an integrin expression inhibitor comprising, asan active ingredient, the sulfonamide compound as described in 5., apharmacologically acceptable salt thereof or a hydrate of them, whereinthe A^(a) ring is a benzene or pyridine which may have a substituent;the B^(a) ring is benzene which may have a substituent; the C^(a) ringis pyrrole which may have a substituent; W^(a) is a single bond; andZ^(a) is —NH—, 11. an integrin expression inhibitor comprising, as anactive ingredient, a sulfonamide-containing heterocyclic compoundrepresented by the formula (I^(b)), a pharmacologically acceptable saltthereof or a hydrate of them:

(in the formula, A^(b) represents hydrogen atom, a halogen atom,hydroxyl group, a C1-C4 alkyl or alkoxy group which may be substitutedwith a halogen atom, cyano group, —(CO)_(k) ^(b)NR^(2b)R^(3b) (whereinR^(2b) and R^(3b) are the same as or different from each other and eachmeans hydrogen atom or a C1-C4 alkyl group which may be substituted witha halogen atom; and k^(b) means 0 or 1), a C2-C4 alkenyl or alkynylgroup which may have a substituent, or a phenyl or phenoxy group whichmay have a substituent selected from the following group A; B^(b) meansan aryl group or monocyclic heteroaryl group which may have asubstituent selected from the following group A, or the followingformula:

(wherein the ring Q^(b) means an aromatic ring which may have one or twonitrogen atoms; and the ring M^(b) means a C5-C12 unsaturated monocycleor heterocycle having a double bond in common with the ring Q^(b). Thering may have 1 to 4 hetero atoms selected from nitrogen atom, oxygenatom and sulfur atom, the ring Q^(b) and the ring M^(b) may jointly havenitrogen atom, and the ring Q^(b) and the ring M^(b) may have asubstituent selected from the following group A); K^(b) means a singlebond or —(CR^(4b)R^(5b))_(m) ^(b)— (wherein R^(4b) and R^(5b) are thesame as or different from each other and each means hydrogen atom or aC1-C4 alkyl group; and m^(b) means an integer of 1 or 2); T^(b), W^(b),X^(b) and Y^(b) are the same as or different from each other and eachmeans ═C(D^(b))- (wherein D^(b) represents hydrogen atom, a halogenatom, hydroxyl group, a C1-C4 alkyl or alkoxy group which may besubstituted with a halogen atom, cyano group, —(CO)_(n)^(b)NR^(6b)R^(7b) (wherein R^(6b) and R^(7b) are the same as ordifferent from each other and each means hydrogen atom or a C1-C4 alkylgroup which may be substituted with a halogen atom; and n^(b) means 0or 1) or a C2-C4 alkenyl or alkynyl group which may have a substituent,respectively) or nitrogen atom; U^(b) and V^(b) are the same as ordifferent from each other and each means ═C(D^(b))- (wherein D^(b) hasthe same meaning as above), nitrogen atom, —CH₂—, oxygen atom or —CO—;Z^(b) means a single bond or —CO—NH—; R^(1b) means hydrogen atom or aC1-C4 alkyl group; and

means a single bond or a double bond.Group A: a halogen atom, hydroxyl group, a C1-C4 alkyl or alkoxy groupwhich may be substituted with a halogen atom, cyano group,—R^(8b)R^(9b)N(NH)_(p) ^(b)— (wherein R^(8b) and R^(9b) are the same asor different from each other and each means hydrogen atom or a C1-C4alkyl group which may be substituted with a halogen atom; and p^(b)means 0 or 1. Further, R^(8b) and R^(9b) may form a 5- or 6-memberedring together with the nitrogen atom to which they are bound, and thering may further contain nitrogen atom, oxygen atom or sulfur atom, andalso may have a substituent.), an aminosulfonyl group which may besubstituted with a mono- or di-C1-C4 alkyl group, a C1-C8 acyl groupwhich may have a substituent, a C1-C4 alkyl-S(O)_(s) ^(b)—C1-C4 alkylenegroup (wherein s^(b) means an integer of 0, 1 or 2), aphenylsulfonylamino group which may have a C1-C4 alkyl or a substituent,—(CO)_(q) ^(b)NR^(10b)R^(11b) (wherein R^(10b) and R^(11b) are the sameas or different from each other and each means hydrogen atom, or a C1-C4alkyl group which may substituted with an amino group which may besubstituted with a halogen atom or a C1-C4 alkyl group; and q^(b) means0 or 1), or an aryl group or heteroaryl group which may have asubstituent), 12. an integrin expression inhibitor comprising, as anactive ingredient, the sulfonamide-containing heterocyclic compound asdescribed in 11., a pharmacologically acceptable salt thereof or ahydrogen of them, wherein U^(b) and V^(b) are ═C(D^(b))- (wherein D^(b)has the same meaning as above) or nitrogen atom, 13. an integrinexpression inhibitor comprising, as an active ingredient, thesulfonamide-containing heterocyclic compound as described in 11. or 12.,a pharmacologically acceptable salt thereof or a hydrate of them,wherein Z^(b) is a single bond, 14. an integrin expression inhibitorcomprising, as an active ingredient, a sulfonamide-containingheterocyclic compound as described in any of 11. to 13., apharmacologically acceptable salt thereof or a hydrate of them, whereinat least one of T^(b), U^(b), V^(b), W^(b), X^(b) and Y^(b) is nitrogenatom, 15. an integrin expression inhibitor comprising, as an activeingredient, the sulfonamide-containing heterocyclic compound asdescribed in any of 11. to 14., a pharmacologically acceptable saltthereof or a hydrate of them, wherein A^(b) represents a halogen atom, aC1-C4 alkyl group or alkoxy group which may be substituted with ahalogen atom, cyano group, —(CO)_(r) ^(b)NR^(12b)R^(13b) (whereinR^(12b) and R^(13b) are the same as or different from each other andeach represents hydrogen atom or a C1-C4 alkyl group which may besubstituted with a halogen atom; and r^(b) means 0 or 1) or a C2-C4alkenyl or alkynyl group which may have a substituent, 16. an integrinexpression inhibitor comprising, as an active ingredient, thesulfonamide-containing heterocyclic compound as described in any of 11.to 15., a pharmacologically acceptable salt thereof or a hydrate ofthem, wherein only one of T^(b), U^(b), V^(b), W^(b), X^(b) and Y^(b) isnitrogen atom, 17. an integrin expression inhibitor comprising, as anactive ingredient, the sulfonamide-containing heterocyclic compound asdescribed in any of 11. to 16., a pharmacologically acceptable saltthereof or a hydrate of them, wherein only one of T^(b), W^(b) and Y^(b)is nitrogen atom, 18. an integrin expression inhibitor comprising, as anactive ingredient, the sulfonamide compound as described in any of 5. to17., a pharmacologically acceptable salt thereof or a hydrate of them,wherein the integrin is integrin α2, α3, α5, α6, αv, β1, β3, β4 or β5,19. an integrin expression inhibitor comprising, as an activeingredient, the sulfonamide compound as described in any of 5. to 17., apharmacologically acceptable salt thereof or a hydrate of them, whereinthe integrin is integrin α2β1, α3β1, α5β1, α6β1, αvβ1, αvβ3 or αvβ5,20. 1) an agent for treating arterial sclerosis, psoriasis, cancer,retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2)an anticoagulant, 3) a cancer metastasis suppressor or 4) anantiangiogenic agent on the basis of an integrin expression inhibitoryaction, which comprises, as an active ingredient, the sulfonamidecompound as described in any of 5. to 17., a pharmacologicallyacceptable salt thereof or a hydrate of them, and 21. 1) an agent fortreating arterial sclerosis, psoriasis or osteoporosis or 2) ananticoagulant on the basis of an integrin expression inhibitory action,which comprises, as an active ingredient, the sulfonamide compound asdescribed in any of 5. to 17., a pharmacologically acceptable saltthereof or a hydrate of them.

The present invention provides a method for preventing, treating orimproving a disease against which an integrin expression inhibition iseffective, by administering a pharmacologically effective dose of thecompound represented by any of formulae (I), (Ia) and (Ib), apharmacologically acceptable salt thereof or a hydrate of them to apatient.

Further, the present invention provides use of the compound representedby any of formulae (I), (Ia) and (Ib), a pharmacologically acceptablesalt of the compound or hydrate of them, for producing an agent forpreventing, treating or improving a disease against which integrinexpression inhibition is effective.

In the present invention, the diseases against which integrin expressioninhibition is effective include arterial sclerosis, psoriasis, cancer,osteoporosis, retinal angiogenesis, diabetic retinopathy andinflammatory diseases.

Also, in the present invention, the agent for preventing, treating orimproving a disease against which an integrin expression inhibition iseffective includes an agent for treating arterial sclerosis, psoriasis,cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy orinflammatory diseases, an anticoagulant agent, a cancer metastasissuppressor and an antiangiogenesis agent.

The present invention will be hereinafter explained in detail.

In B and R, the C6-C10 aryl ring or 6-membered to 10-membered heteroarylring which may have a substituent and in which a part of the ring may besaturated means an aromatic hydrocarbon group having 6 to 10 carbonatoms or a 6-membered to 10-membered aromatic heterocycle containing atleast one atom among nitrogen atom, oxygen atom and sulfur atom as aheteroatom, and may have one or more substituents on the ring and a partof the ring may be saturated. Specific examples thereof include benzene,pyridine, pyrimidine, pyrazine, pyridazine, naphthalene, quinoline,isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline,cinnoline, indole, isoindole, indolizine, indazole, benzofuran,benzothiophene, benzoxazole, benzimidazole, benzopyrazole,benzothiazole, 4,5,6,7-tetrahydroindole, 1,2,3,4-tetrahydroisoquinoline,2,3-dihydrobenzofuran, indane, tetralone, indoline, isoindoline, chromanand tetralin. The above-mentioned aromatic ring may have 1 to 3substituents. In the case where plural substituents are present, thesesubstituents may be the same or different. Examples of the substituentmay include an amino group which may be substituted with a lower alkylgroup or lower cycloalkyl group, a lower alkyl group, a lower alkoxygroup, hydroxyl group, nitro group, mercapto group, cyano group, a loweralkylthio group, a halogen group, a group represented by the formula-a^(a)-b^(a) (wherein a^(a) means a single bond, —(CH₂)_(k) ^(a)—,—O—(CH₂)_(k) ^(a)—, —S—(CH₂)_(k) ^(a)— or —N(R^(3a))—(CH₂)_(k) ^(a)—(wherein k^(a) means an integer of 1 to 5; and R^(3a) means hydrogenatom or a lower alkyl group); and b^(a) means —CH₂-d^(a) (wherein d^(a)means an amino group which may be substituted with a lower alkyl group,a halogen atom, hydroxyl group, a lower alkylthio group, cyano group orlower alkoxy group)), a group represented by the formula-a^(a)-e^(a)-f^(a) (wherein a^(a) has the same meaning as above; e^(a)means —S(O)— or —S(O)₂—; and f^(a) means an amino group which may besubstituted with a lower alkyl group or lower alkoxy group, a loweralkyl group, trifluoromethyl group, —(CH₂)_(m) ^(a)-b^(a) or—N(R^(4a))—(CH₂)_(m) ^(a)-b^(a) (wherein b^(a) has the same meaning asabove; R^(4a) means hydrogen atom or a lower alkyl group; and m^(a)means an integer from 1 to 5)), a group represented by the formula-a^(a)-g^(a)-h^(a) (wherein a^(a) has the same meaning as above; g^(a)means —C(O)— or —C(S)—; and h^(a) means an amino group which may besubstituted with a lower alkyl group, hydroxyl group, a lower alkylgroup, a lower alkoxy group, —(CH₂)_(n) ^(a)-b^(a) or—N(R^(5a))—(CH₂)_(n) ^(a)-b^(a) (wherein b^(a) has the same meaning asabove; R^(5a) means hydrogen atom or a lower alkyl group; and n^(a)means an integer from 1 to 5)), a group represented by the formula-a^(a)-N(R^(6a))-g^(a)-i^(a) (wherein a^(a) and g^(a) have the samemeanings as above; R^(6a) means hydrogen atom or a lower alkyl group;i^(a) means hydrogen atom, a lower alkoxy group or f^(a) (f^(a) has thesame meaning as above)), a group represented by the formula-a^(a)-N(R^(7a))-e^(a)-f^(a) (wherein a^(a), e^(a) and f^(a) have thesame meanings as above; R^(7a) means hydrogen atom or a lower alkylgroup), the formula —(CH₂)_(p) ^(a)-j^(a)-(CH₂)_(q) ^(a)-b^(a) (whereinj^(a) means oxygen atom or a sulfur atom; b^(a) has the same meaning asabove; and p^(a) and q^(a) are the same as or different from each otherand each means an integer from 1 to 5), the formula —(CH₂)_(u)^(a)—Ar^(a) (wherein Ar^(a) means a phenyl group or heteroaryl groupwhich may be substituted with a lower alkyl group, lower alkoxy group orhalogen atom; and u^(a) means 0 or an integer from 1 to 5), the formula—CONH—(CH₂)_(u) ^(a)—Ar^(a) (wherein Ar^(a) and u^(a) have the samemeanings as above) or a group represented by the formula —SO₂—(CH₂)_(u)^(a)—Ar^(a) (wherein Ar^(a) and u^(a) have the same meanings as above).

Compounds represented by the formula (I), in which R is indole,quinoline or isoquinoline, are preferable.

In the formula (I^(a)), the “monocyclic or bicyclic aromatic ring whichmay have a substituent” represented by the A^(a) ring is an aromatichydrocarbon or an aromatic heterocycle containing at least one ofnitrogen atom, oxygen atom and sulfur atom, wherein 1 to 3 substituentsmay exist on the ring. Examples of main aromatic rings contained in theA^(a) ring include pyrrole, pyrazole, imidazole, thiophene, furan,thiazole, oxazole, benzene, pyridine, pyrimidine, pyrazine, pyridazine,naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, indole, isoindole, indolizine,indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole,benzopyrazole and benzothiazole. The above-mentioned aromatic ring mayhave 1 to 3 substituents. When plural substituents are present, thesesubstituents may be the same or different. Examples of the substituentmay include an amino group which may be substituted with a lower alkylgroup or a lower cycloalkyl group, lower alkyl group, lower alkoxygroup, hydroxyl group, nitro group, mercapto group, cyano group, loweralkylthio group, halogen group, a group represented by the formula-a^(a)-b^(a) (wherein a^(a) means a single bond, —(CH₂)_(k) ^(a)—,—O—CH₂)_(k) ^(a)—, —S—(CH₂)_(k) ^(a)— or —N(R^(3a))—(CH₂)_(k) ^(a)—;k^(a) means an integer of 1 to 5; R^(3a) means hydrogen atom or a loweralkyl group; and b^(a) represents —CH₂-d^(a) (where d^(a) means an aminogroup which may be substituted with a lower alkyl group, a halogen atom,hydroxyl group, a lower alkylthio group, cyano group or a lower alkoxygroup)), a group represented by the formula -a^(a)-e^(a)-f^(a) (whereina^(a) has the same meaning as above; e^(a) means —S(O)— or —S(O)₂—;f^(a) means an amino group which may be substituted with a lower alkylgroup or lower alkoxy group, a lower alkyl group, trifluoromethyl group,—(CH₂)_(m) ^(a)-b^(a) or —N(R^(4a))—(CH₂)_(m) ^(a)-b^(a) (wherein b^(a)has the same meaning as above; R^(4a) means hydrogen atom or a loweralkyl group; and m^(a) means an integer from 1 to 5)), a grouprepresented by the formula -a^(a)-g^(a)-h^(a) (wherein a^(a) has thesame meaning as above; g^(a) means —C(O)— or —C(S)—; h^(a) means anamino group which may be substituted with a lower alkyl group, hydroxylgroup, a lower alkyl group, a lower alkoxy group, —(CH₂)_(n) ^(a)-b^(a)or —N(R^(5a))—(CH₂)_(n) ^(a)-b^(a) (wherein b^(a) has the same meaningas above; R^(5a) means hydrogen atom or a lower alkyl group; and n^(a)means an integer from 1 to 5)), a group represented by the formula-a^(a)-N(R^(6a))-g^(a)-i^(a) (wherein a^(a) and g^(a) have the samemeanings as above; R^(6a) means hydrogen atom or a lower alkyl group;and i^(a) means hydrogen atom, a lower alkoxy group or f^(a) (f^(a) hasthe same meaning as above)), a group represented by the formula-a^(a)-N(R^(7a))-e^(a)-f^(a) (wherein a^(a), e^(a) and f^(a) have thesame meanings as above; and R^(7a) means hydrogen atom or a lower alkylgroup), the formula —(CH₂)_(p) ^(a)-j^(a)-(CH₂)_(q) ^(a)-b^(a) (whereinj^(a) means oxygen atom or sulfur atom; b^(a) has the same meaning asabove; and p^(a) and q^(a) are the same as or different from each otherand each means an integer from 1 to 5), the formula —(CH₂)_(u)^(a)—Ar^(a) (wherein Ar^(a) means a phenyl group or heteroaryl groupwhich may be substituted with a lower alkyl group, lower alkoxy group orhalogen atom; and u^(a) means 0 or an integer from 1 to 5), the formula—CONH—(CH₂)_(u) ^(a)—Ar^(a) (wherein Ar^(a) and u^(a) have the samemeanings as above) or a group represented by the formula —SO₂—(CH₂)_(u)^(a)—Ar^(a) (wherein Ar^(a) and u^(a) have the same meanings as above).

In the aforementioned examples of the substituent, when the amino groupis substituted with two alkyl groups, these alkyl groups may be boundtogether to form a 5- to 6-membered ring. Further, in the case where theA^(a) ring is a nitrogen-containing heterocycle having hydroxyl group ormercapto group, the A^(a) ring may have the form of an oxo group orthioxo group by allowing these groups to form a resonance structure.

The “6-membered cyclic unsaturated hydrocarbon or the unsaturatedsix-membered heterocycle which contains one nitrogen atom as aheteroatom, which may have a substituent” represented by the B^(a) ringis a benzene or pyridine a part of which may be hydrogenated and mayhave one or two substituents on the ring. When two substituents arepresent, these substituents may be the same or different.

The “five-membered heterocycle which may have a substituent and containsone or two nitrogen atoms” represented by the C^(a) ring is pyrrole,pyrazole or imidazole a part of which may be hydrogenated and may haveone or two substituents on the ring. When two substituents are present,these substituents may be the same or different.

Examples of the substituent which the B^(a) ring and the C^(a) ring mayhave may include a halogen group, cyano group, a lower alkyl group, alower alkoxy group, hydroxyl group, oxo group, the formula —C(O)-r^(a)(wherein r^(a) means hydrogen atom, an amino group which may besubstituted with a lower alkyl group, a lower alkyl group, a loweralkoxy group or hydroxyl group), an amino group which may be substitutedwith a lower alkyl group and trifluoromethyl group.

Examples of the lower alkyl group in the definition of the substituentwhich R^(1a), R^(2a), and the A^(a), B^(a) and C^(a) rings may have inthe above formula (I^(a)) mean a linear or branched alkyl group having 1to 6 carbon atoms, for example, methyl group, ethyl group, n-propylgroup, isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, n-pentyl group (amyl group), isopentyl group,neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutylgroup, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group,1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group,3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,1-ethyl-1-methylpropyl group and 1-ethyl-2-methylpropyl group. Aspreferable groups among these groups, methyl group, ethyl group,n-propyl group, isopropyl group, n-butyl group and isobutyl group may beproposed. Among these preferable groups, methyl group, ethyl group,n-propyl group and isopropyl group are most preferable groups.

Examples of the lower cycloalkyl group in the definition of thesubstituent which the Aa ring may have include a cyclopropyl group,cyclopentyl group and cyclohexyl group.

The lower alkoxy group in the definition of the substituent which theA^(a) ring, the B^(a) ring and the C^(a) ring may have means a loweralkoxy groups derived from the above-mentioned lower alkyl groups suchas methoxy group, ethoxy group, n-propoxy group, isopropoxy group,n-butoxy group, isobutoxy group and tert-butoxy group. Among thesegroups, methoxy group and ethoxy group may be given as most preferableexamples. Also, examples of the halogen atom include fluorine atom,chlorine atom and bromine atom.

Among these substituents, particularly preferable examples include 1)N-(3-cyano-4-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide; 2)N-(3-cyano-4-methyl-1H-indole-7-yl)-6-chloro-3-pyridinesulfonamide; 3)N-(3-bromo-5-methyl-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide; 4)N-(5-bromo-3-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide; 5)N-(3-bromo-5-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide; 6)N-(4-bromo-1H-indole-7-yl)-4-cyanobenzenesulfonamide; 7)N-(4-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide; 8)N-(3-bromo-4-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide; 9)N-(3-bromo-5-methyl-1H-indole-7-yl)-5-cyano-2-thiophenesulfonamide; 10)N-(4-bromo-3-chloro-1H-indole-7-yl)-2-amino-5-pyrimidinesulfonamide; and11) N-(3-chloro-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide.

There is the case where the sulfonamide derivative represented by theabove formula (I^(a)) forms a salt in combination with an acid or abase. The present invention also involves salts of the compound (I^(a)).Examples of the salt of an acid include inorganic acid salts such ashydrochloride, hydrobromide and sulfate, and salts of organic acids suchas acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid,citric acid, benzoic acid, methanesulfonic acid and p-toluenesulfonicacid. Examples of the salt of a base may include inorganic salts such assodium salts, potassium salts and calcium salts and salts of organicbases such as triethylamine, arginine and lysine.

In the present invention, the “aromatic ring which may have one or twonitrogen atoms” represented by the ring Q^(b) means an aromatichydrocarbon or a 6-membered aromatic heterocycle having one or twonitrogen atoms. Examples of primary aromatic rings included in the ringQ^(b) include benzene, pyridine, pyrimidine, pyrazine and pyridazine.Also, the ring M represented by the term “means a C5-C12 unsaturatedmonocycle or multi-cycle, which may have 1 to s4 heteroatoms selectedfrom nitrogen atom, oxygen atom and sulfur atom” means a monocycle or amulti-cycle having a double bond together with the ring Q^(b) andspecifically means aromatic hydrocarbons such as benzene andnaphthalene, unsaturated hydrocarbons such as cyclopentene, cyclohexene,cycloheptene, cyclooctene, cyclopentadiene, cycloheptadiene andcyclooctadiene, and unsaturated heterocycles such as tetrahydropyridine,pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole,pyrazole, imidazole, triazole, pyridine, pyrimidine, pyrazine,pyridazine, triazine, indole, isoindole, quinoline, isoquinoline,indazolizine, naphthyridine, benzofuran, benzopyran, benzothiophene,benzimidazole benzoxazole, benzothiazole, pyrrolopyridine,pyridopyrimidine and imidazopyridine. Also, the term “the ring Q^(b)possesses one nitrogen atom together with the ring M^(b)” means the casewhere the nitrogen atom is present at the position where both rings arecondensed. Examples of the ring formed in this manner includeindazolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine andpyrazolo[1,5-a]pyrimidine.

In the present invention, the C1-C4 alkyl group in R^(1b), R^(4b) andR^(5b) or in the “C1-C4 alkyl group which may be substituted with ahalogen atom” in A^(b), D^(b), R^(1b), R^(2b), R^(3b), R^(6b), R^(7b),R^(8b), R^(9b), R^(10b), R^(11b), R^(12b), R^(13b), R^(14b), R^(15b),G^(1b), G^(2b) and the A group means a linear or branched alkyl grouphaving 1 to 4 carbons atoms. For example, methyl group, ethyl group,n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group and tert-butyl group may be proposed. The term “may besubstituted with a halogen atom” means that the alkyl group may besubstituted with a halogen atom selected from fluorine atom, chlorineatom, bromine atom and iodine atom. For example, monofluoromethyl group,monochloromethyl group, difluoromethyl group, trifluoromethyl group, 1-or 2-monofluoromethyl group, 1- or 2-monochloroethyl group, 1- or2-monobromoethyl group, 1,2-difluoroethyl group, 1,2-dichloroethylgroup, 1,1,2,2,2-pentafluoroethyl group and 3,3,3-trifluoropropyl groupmay be proposed. Preferable examples among these groups includemonofluoromethyl group, difluoromethyl group, trifluoromethyl group, 1-or 2-monofluoroethyl group, 1,2-difluoroethyl group and1,1,2,2,2-pentafluoroethyl group.

In the present invention, the C1-C4 alkoxy group in the “C1-C4 alkoxygroup which may be substituted with a halogen atom” in A^(a), D^(b) andthe group A means a linear or branched alkoxy group having 1 to 4 carbonatoms. For example, methoxy group, ethoxy group, n-propyloxy group,isopropyloxy group, n-butyloxy group, isobutyloxy group, sec-butyloxygroup and tert-butyloxy group may be proposed. The term “may besubstituted with a halogen atom” means that the alkoxy group may besubstituted with a halogen atom selected from fluorine atom, chlorineatom, bromine atom and iodine atom. For example, monofluoromethoxygroup, difluoromethoxy group, trifluoromethoxy group, 1- or2-monofluoroethoxy group, 1- or 2-monochloroethoxy group, 1- or2-monobromoethoxy group, 1,2-difluoroethoxy group,1,1,2,2,2-pentafluoroethoxy group and 3,3,3-trifluoropropyloxy group maybe proposed. Among these groups, preferable examples includemonofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group,1- or 2-monofluoroethoxy group, 1,2-difluoroethoxy group and1,1,2,2,2-pentafluoroethoxy group.

In the present invention, the C2-C4 alkenyl or alkynyl group appeared inA^(b) and D^(b) means an alkenyl or alkynyl group having 2 to 4 carbonatoms. For example, vinyl group, allyl group, 2- or 3-butenyl group,1,3-butadienyl group, ethynyl group, 2-propynyl group, 2-methylethynylgroup and 2- or 3-butynyl group may be proposed.

In the present invention, the aryl group appeared in B^(b) and the groupA means an aromatic hydrocarbon, and phenyl group and naphthyl group maybe exemplified. Also, the heteroaryl group means a monocycle ormulti-cycle having one or two or more of nitrogen atom, oxygen atom andsulfur atom. For example, pyrrolyl, imidazolyl group, pyrazolyl group,triazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolylgroup, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyridylgroup, pyrimidyl group, pyrazyl group, indolyl group, indolizinyl group,benzoimidazolyl group, benzothiazolyl group, benzoxazolyl group,quinolinyl group, isoquinolinyl group, quinazolinyl group andphthalazinyl group may be proposed.

In the present invention, the term “R^(8b) and R^(9b) may form a 5- or6-membered ring together with the nitrogen atom to which they are bound,and the ring may further contain nitrogen atom, oxygen atom or sulfuratom” in the definition of R^(8b) and R^(9b) means that R^(8b) andR^(9b) form pyrrolidinyl group, piperidinyl group, morpholino group,thiomorpholino group, piperazinyl group etc. together with the nitrogenatom to which they are bound.

In the present invention, the aminosulfonyl group which may besubstituted with a mono- or di-C1-C4 alkyl group, C1-C4 alkyl-S(O)_(s)^(b)-C1-C4-alkylene group, or phenylsulfonylamino group which may have aC1-C4 alkyl group or a substituent and a C1-C4 alkyl group which may besubstituted with a C1-C4 alkyl group in the definition of A group meansthe same alkyl group as above, and examples of the alkylene group mayinclude methylene group, ethylene group, propylene group, butylenegroup, methylmethylene group, 1- or 2-methylethylene group, 1-, 2- or3-methylpropylene group and dimethylmethylene group.

Also, the C1-C8 alkanoyl group means, for example, formyl group, acetylgroup, propionyl group, butyryl group, isobutyryl group, valeryl groupand benzoyl group.

The protective group in the term “an amino group which may have aprotective group” appeared in J^(b) of the present invention may be anygroup as far as it is known as a protective group in the usual organicsynthesis and no particular limitation is imposed on the protectivegroup. For example, benzyloxycarbonyl group, t-butoxycarbonyl group,formyl group, acetyl group, chloroacetyl group, 2,2,2-trichloroethylgroup, benzylidene group, benzhydryl group and trityl group may beproposed. Also, the protective group in the carboxy group which may havea protective group and the protective group of the carboxy group inR^(16b) may be any group as far as it is known as a protective group inthe usual organic synthesis and no particular limitation is imposed onthe protective group. For example, methyl group, ethyl group, propylgroup, isopropyl group, t-butyl group, methoxymethyl group,2,2,2-trichloroethyl group, pivaloyloxymethyl group and benzyl group maybe proposed.

In the present invention, the substituent in the term “may have asubstituent” means the above-mentioned halogen atom, C1-C4 alkyl groupor alkoxy group which may be substituted with a halogen atom, hydroxylgroup, hydroxy C1-C4 alkyl group, amino group which may be substitutedwith a mono- or di- C1-C4 alkyl group, C2-C4 alkenyl or alkynyl group,cyano group, C1-C8 acyl group, aminosulfonyl group which may besubstituted with a mono or di C1-C4 alkyl group, carboxy group, C1-C4alkoxycarbonyl group and carbamoyl group which may be substituted with amono- or di-C1-C4 alkyl group.

The sulfonamide-containing heterocyclic compound represented by theabove formula (I^(b)) occasionally forms a salt in combination with anacid or a base. The present invention also includes salts of thecompound (I^(b)). Examples of the salt of an acid include inorganic acidsalts such as hydrochloride, hydrobromide and sulfate and salts oforganic acids such as acetic acid, lactic acid, succinic acid, fumaricacid, maleic acid, citric acid, benzoic acid, methanesulfonic acid andp-toluenesulfonic acid. Also, as the salt of a base, inorganic saltssuch as sodium salts, potassium salts and calcium salts and salts oforganic bases such as triethylamine, arginine and lysine may be given.

Also, it is needless to say that as well as hydrates of these compounds,optical isomers, if these isomers are present, are included in thepresent invention. The present invention also includes compounds showingan antiangiogenesis action and produced from the present compoundfollowing in vivo metabolism such as oxidation, reduction, hydrolysisand conjugation. Also, the present invention further includes compoundsproducing the compound of the present invention following in vivometabolism such as oxidation, reduction and hydrolysis.

The compound (I^(a)) according to the present invention can be producedby various methods. For example, several methods among these methods arespecifically disclosed in the publications of JP-A 7-165708 and JP-A8-231505.

As aforementioned, the compound (I^(a)) of the present invention may beproduced using various methods. Among these methods, typical methods areshown as follows.

1) It may be produced by reacting a sulfonic acid represented by theformula (II^(a)):

(wherein the Aa^(a) ring represents a monocyclic or bicyclic aromaticring which may have a protected or unprotected substituent; and W^(a)has the same meaning as above) or its reactive derivative with acompound represented by the formula (III^(a)):

wherein the Ba^(a) ring represents a 6-membered unsaturated hydrocarbonor unsaturated 6-membered heterocycle which contains on nitrogen atom asa heteroatom, which may have a protected or unprotected substituent; theCa^(a) ring a 5-membered ring which may have a protected or unprotectedsubstituent and contains one or two nitrogen atoms; and X^(a), Y^(a) andZ^(a) have the same meanings as above.

Examples of the reactive derivative of the sulfonic acid (II^(a)) mayinclude reactive derivatives usually used frequently such as sulfonylhalides, sulfonic acid anhydrides and N-sulfonylimidazolides.Particularly preferable examples are sulfonyl halides. Although noparticular limitation is imposed on the solvent used in the reaction, itis desirable to use a solvent which dissolves raw materials and does notreact with these raw materials with ease. For example, pyridine,tetrahydrofuran, dioxane, benzene, ethyl ether, dichloromethane anddimethylformamide, or a mixed solvent using two or more solventsselected from these solvents may be utilized. Also, in the reaction, inthe case where a free acid appears with the progress of the reaction asshown in the case of using a sulfonyl halide, the reaction is preferablyrun in the presence of a proper deoxidizer. Therefore, the use of abasic solvent such as pyridine is particularly preferable. When aneutral solvent is used, a basic substance such as an alkali carbonateand an organic tertiary amine may be added. It is needless to say thatusable solvents are not limited to these exemplified solvents. Althoughthe reaction generally proceeds at room temperature, the raw materialsmay be cooled or heated according to the need. The reaction time isgenerally 10 minutes to 20 hours but is selected according to the typeof raw material and the reaction temperature.

In the case where the amino group or the hydroxyl group is protected inthe resulting product, a sulfonamide derivative or sulfonate derivative(I^(a)) having a free hydroxyl group or amino group can be obtained by ausual deprotecting method such as acid treatment, alkali treatment andcatalytic reduction, as required.

2) It may be produced by reacting a compound represented by the formula(IV^(a)):

(wherein the Aa^(a) ring, the Ba^(a) ring, W^(a), X^(a) and Z^(a) havethe same meanings as above) with a halogenating agent. As thehalogenating agent, N-chlorosuccinimide, N-bromosuccinimide,1,3-dibromo-5,5-dimethylhydantoin, N-bromoacetamide, chlorine andbromine may be proposed. Although no particular limitation is imposed onthe solvent to be used in the reaction, an alkyl chloride compound suchas dichloromethane, chloroform and carbon tetrachloride, or an aromaticchloride such as chlorobenzene and dichlorobenzene is generally used,and a water-soluble solvent such as dimethylformamide, dioxane, pyridineand acetonitrile may be also used. Although the reaction temperaturediffers depending on the types of halogenating agent and substrate, itis usually run at −50° C. to 100° C.

In the case where the amino group or the hydroxyl group is protected inthe resulting product, a sulfonamide derivative or sulfonate derivative(I^(a)) having a free hydroxyl group or amino group can be obtained by ausual deprotecting method such as acid treatment, alkali treatment andcatalytic reduction, as required.

3) It may be produced by reacting a compound represented by the formula(V^(a)):

(wherein the Aa^(a) ring, the Ba^(a) ring, W^(a), X^(a) and Z^(a) havethe same meanings as above; and E^(a) represents a substituentconvertible into cyano group by dehydration) with a dehydrating agent.As the substituent convertible into cyano group by dehydration,(hydroxyimino)methyl group and carbamoyl group may be proposed.

Also, it is possible that an oxime or an acid amide is first synthesizedfrom an aldehyde or a carboxylic acid used as a starting material andthen reacted with a dehydrating agent without isolating it. As examplesof the dehydrating agent, those used in a usual method of synthesizingnitrile, for example, acetic acid anhydride, thionyl chloride,phosphorous oxychloride, selenium dioxide and1,3-dicyclohexylcarbodiimide may be given. Although no particularlimitation is imposed on the solvent to be used in the reaction, thosewhich do not react with these materials with ease is desirable, forexample pyridine, ethyl ether, benzene, dimethylformamide, carbontetrachloride, acetonitrile and tetrahydrofuran, or a mixed solvent oftwo or more solvents selected from these solvents may be utilized.Although the reaction temperature differs depending on the types ofdehydrating agent and substrate, the reaction is usually run at −50° C.to 150° C.

In the case where the amino group or the hydroxyl group is protected inthe resulting product, a sulfonamide derivative or sulfonate derivative(I^(a)) having a free hydroxyl group or amino group can be obtainedusing a usual deprotecting method such as acid treatment, alkalitreatment and catalytic reduction, as required.

4) It may be produced by reacting a compound represented by the formula(VI^(a)):

(wherein the Ab^(a) ring represents a monocyclic or bicyclic aromaticring which has a substituent convertible into amino group by reductionand may also have a protected or unprotected substituent; and the Ba^(a)ring, the Ca^(a) ring, W^(a), X^(a), Y^(a) and Z^(a) have the samemeanings as above) with a reducing agent. As the substituent convertibleinto amino group by reduction, nitro group, nitroso group, hydroxyaminogroup and azo group may be exemplified.

A nitro group-reducing method which is commonly examples of the reducingmethod, catalytic reduction using, as a catalyst, palladium-carbon andplatinum oxide and reduction using zinc, iron or tin with an acid may begiven. The catalytic reduction may be usually carried out under normalpressure or under pressure in an organic solvent such as methanol,tetrahydrofuran or dimethylformamide.

In the case where the hydroxyl group is protected in the resultingproduct, a sulfonamide derivative or sulfonate derivative (I^(a)) havinga free hydroxyl group can be obtained using a usual deprotecting methodsuch as acid treatment, alkali treatment and catalytic reduction, asrequired.

5) It may be produced by reacting a compound represented by the formula(VII^(a)):

(wherein the Ac^(a) ring means a monocyclic or bicyclic aromatic ringwhich has a dissociable group on the ring or in a substituent, and mayalso have a protected or unprotected substituent; and the Ba^(a) ring,the Ca^(a) ring, W^(a), X^(a), Y^(a) and Z^(a) have the same meanings asabove) with a nucleophilic agent. Examples of the leaving group mayinclude a halogen group, methanesulfonyloxy group andp-toluenesulfonyloxy group. Examples of the nucleophilic agent mayinclude amines, alcohols and thiols. In the case of alcohols or thiols,these compounds may have the form of a salt of an alkali metal or thelike upon reaction. Although no particular limitation is imposed on thesolvent to be used in the reaction, a solvent which dissolves rawmaterials and does not react with these materials with ease isdesirable. For example, tetrahydrofuran, dioxane, dimethylformamide orwater may be utilized. Although the reaction temperature differsdepending on the type of substrate, the reaction is usually run at −50°C. to 150° C.

In the case where the amino group or the hydroxyl group is protected inthe resulting product, a sulfonamide derivative or sulfonate derivative(I^(a)) having a free hydroxyl group or amino group can be obtained by ausual deprotecting method such as acid treatment, alkali treatment andcatalytic reduction, as required.

Next, methods for producing the raw material compound (II^(a)) and itsreactive derivative and the compound (III^(a)) used in the presentinvention will be explained.

The raw material compound (II^(a)) and its reactive derivative includeknown compounds and novel compounds. In the case of these novelcompounds, these compounds may be produced by applying a method ofsynthesizing a known compound which has been already reported or byusing a combination of these known methods. For example, a novelsulfonyl chloride may be produced by a method obtained by applyingsynthetic methods described in Chem. Ber., 90, 841 (1957), J. Med.Chem., 6, 307 (1963), J. Chem. Soc.(c), 1968, 1265, Chem. Lett., 1992,1483, J. Am. Chem. Soc., 59, 1837 (1937), J. Med. Chem., 23, 1376(1980), J. Am. Chem. Soc., 70, 375 (1948), J. Am. Chem. Soc., 78, 2171(1956) etc.

The raw material compound (III^(a)) includes known compounds and novelcompounds. In the case where H—X^(a)— represents an amino group H₂N— inthe raw material compound (III^(a)), an H₂N body (III^(a)) can beobtained by reducing the nitro compound by using a nitro group-reducingmethod which is usually used. Preferable examples of the reducingmethods include catalytic reduction using a palladium-carbon catalystand reduction using a zinc powder-hydrochloric acid. The catalyticreduction may be usually carried out under normal pressure or underpressure in an organic solvent such as methanol, tetrahydrofuran anddimethylformamide.

In the case where H—X^(a)— means hydroxyl group (HO—) in the rawmaterial compound (III^(a)), a HO compound (III^(a)) can be obtained bydiazotizing the above amino compound and then hydrolyzing the resultingproduct.

In the case where the raw material compounds are these novel compounds,these compounds may be produced by applying a method of synthesizing aknown compound which has been already reported or by using a combinationof these known methods. A novel compound may be produced by applying themethods described in Can. J. Chem., 42, 1235 (1964), Chem. Abst., 59,8855f (1963), Tetrahedron Lett., 30, 2129 (1989) etc. through, forexample, the following route.

In the formula, Q^(a)s mean the same or different substituents; G^(a)means a halogen group; and t^(a) means an integer from 0 to 2.

In the formula, Q^(a) and t^(a) have the same meanings as above.

In the formula, Q^(a), G^(a) and t^(a) have the same meanings as above;and DPPA means diphenylphosphorylazide.

In the formula, Q^(a), G^(a) and t^(a) have the same meanings as above;and DDQ means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Next, the compound (I^(b)) of the present invention may be produced byvarious methods. Among them, typical methods are as follows.

1) When Z^(b) is a single bond

In the formula, A^(b), B^(b), T^(b), U^(b), V^(b), W^(b), X^(b) andT^(b) have the same meanings as above. It may be produced by reactingthe sulfonic acid represented by the formula (V^(b)) or its reactivederivative with the compound represented by the formula (VI^(b)).

As examples of the reactive derivative of the sulfonic acid (V^(b)),reactive derivatives generally utilized frequently such as sulfonylhalides, sulfonic acid anhydrides and N-sulfonylimidazolides may beproposed. A particularly preferable example is a sulfonyl halide.Although no particular limitation is imposed on the solvent to be usedin the reaction, those which dissolve the raw material and do not reactwith the raw material with ease are desirable. For example, pyridine,tetrahydrofuran, dioxane, benzene, ethyl ether, dichloromethane anddimethylformamide, or a mixed solvent of two or more solvents selectedfrom these may be utilized. Also, in this reaction, in the case where afree acid appears with the progress of the reaction as shown in the caseof using a sulfonyl halide, the reaction is preferably run in thepresence of a proper deoxidizer. Therefore, the use of a basic solventsuch as pyridine is particularly preferable. When a neutral solvent isused, a basic substance such as an alkali carbonate and an organictertiary amine may be added. It is needless to say that usable solventsare not limited to these exemplified solvents. Although this reactiongenerally proceeds at room temperature, the raw materials may be cooledor heated according to the need. The reaction time is generally 10minutes to 20 hours but is optionally selected according to the type ofraw material and the reaction temperature.

In the case where the amino group or the hydroxyl group is protected inthe resulting product, a sulfonamide derivative (VII^(b)) having a freehydroxyl group or amino group can be obtained using a usual deprotectingmethod such as acid treatment, alkali treatment and catalytic reduction,as required.

2) When Z^(b) is —CO—NH—

In the formula, L^(b) means chlorine atom or bromine atom; R^(17b)represents a C1-C4 alkyl group or benzyl group; and A^(b), B^(b), T^(b),U^(b), V^(b), W^(b), X^(b) and T^(b) have the same meanings as above.

It may be produced by reacting a compound represented by the formula(VIII^(b)) isocyanate with a sulfonamide compound represented by theformula (IX^(b)).

The reaction is run in water or a water-miscible non-reactive solventsuch as tetrahydrofuran and acetone in the presence of a base such assodium hydroxide, potassium hydroxide, lithium hydroxide, sodiummethoxide and sodium hydride. The reaction is run at a temperature from0° C. up to 100° C. and preferably about 20 to 30° C.

Another preferable reaction is attained by a method in which an aminerepresented by the formula (XI^(b)) is reacted with a carbamaterepresented by the formula (XII^(b)) obtained by reacting a sulfonamiderepresented by the formula (IX^(b)) with a haloformate represented bythe formula (XIII^(b)).

The reaction between the sulfonamide represented by the formula (IX^(b))with the haloformate represented by the formula (XIII^(b)) is run in anon-reactive solvent such as acetone, tetrahydrofuran and methyl ethylketone in the presence of an acid scavenger such as potassium carbonate,sodium carbonate, potassium hydroxide and sodium hydroxide. The reactionis run at a temperature from about 30° C. to a refluxing temperature.Next, the reaction between the carbamate represented by the formula(XII^(b)) and the amine represented by the formula (XI^(b)) is run in aninert and high-boiling point solvent such as dioxane, toluene and diglymunder heating at a temperature from about 50° C. to a refluxingtemperature.

The amine compound represented by the formula (VI^(b)) or (XI^(b)) asthe raw material of the sulfonamide or sulfonylurea-containingheterocyclic compound of the present invention may be produced using acombination of known methods.

For example, quinoline and isoquinoline derivatives may be produced inthe following production steps.

In the formula wherein A^(b), E^(2b), G^(2b) and R^(16b) have the samemeanings as above; and R^(18b) means a C1-C4 alkyl group or benzylgroup.

In the formula, A^(b) and G^(2b) have the same meanings as above.

In the formula, R^(18b) has the same meaning as above; and R^(19b) meansa C1-C4 alkyl group.

In the formula, R^(18b) and E^(2b) have the same meanings as above;R^(20b) and R^(21b) respectively means hydrogen atom or a C1-C4 alkylgroup; R^(22b) represents a C1-C4 alkoxy group, a phenoxy group orphenyl group which may have a substituent, cyano group or an amino groupwhich may be substituted with a mono- or di-C1-C4 alkyl group; andE^(3b) represents hydrogen atom, a halogen atom, a C1-C4 alkoxy group, aphenoxy group or phenyl group which may have a substituent, cyano groupor an amino group which may be substituted with a mono- or di-C1-C4alkyl group.

When the compound of the present invention is used as drugs, it isadministered orally or parenterally. The dose of the compound differsdepending on the degree of symptoms, the ages, sexes, weights and adifference in sensitivity of patients, the administration method, thetime of administration, administration interval, the features of drugpreparations, prescription and types of drug preparations, the types ofactive ingredients etc. and no particular limitation is imposed on thedose. However, the dose is generally 10 to 6000 mg, preferably about 50to 4000 mg and more preferably 100 to 3000 mg per day for an adult andthe drug is generally administered at the defined dose in one to threeprotons a day.

When preparing oral solid preparations, a filler and further, asrequired, a binder, a disintegrator, a lubricant, a colorant and aflavoring agent were added to a base drug and then the mixed drugs aremade into tablets, coated tablets, granules, fine granules, powders orcapsule agents.

As the filler, for example, lactose, cornstarch, saccharose, glucose,sorbitol, crystalline cellulose or silicon dioxide; as the binder, forexample, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gumarabic, hydroxypropyl cellulose or hydroxypropylmethyl cellulose; as thelubricant, for example, magnesium stearate, talc or silica; as thecolorant, those permitted to be added to drugs; and as the flavor, cocoapowder, menthol, aromatic acid, peppermint oil, borneol, cinnamon powderetc. is used. These tablets and granules may be provided with sugarcoating or gelatin coating and in addition, may be properly coated asrequired.

In the case of preparing injections, a pH regulator, a buffer, asuspending agent, a solubilizer, a stabilizer, an isotonic agent, apreservative etc. are added to a base drug according to the need and themixture is then made into intravenous injections, subcutaneousinjections or intramuscular injections by a usual method. At this time,these injections are occasionally made into freeze-dried products.

Examples of the suspending agent may include methyl cellulose,polysorbate 80, hydroxyethyl cellulose, gum arabic, traganth powder,carboxymethyl cellulose sodium and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizer may include polyoxyethylene hydrogenatedcastor oil, polysorbate 80, nicotinic acid amide, polyoxyethylenesorbitan monolaurate, macrogol and castor oil fatty acid ethyl ester.

Also, examples of stabilizers may include sodium sulfite and sodiummethasulfite; and examples of the preservative may include methylparaoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol andchlorocresol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows, on the upper side, the results obtained by measuring thequantity of integrin expression after 48 hours when using a compound A(untreated and 0.05 μg/ml) for human umbilical venous endothelial cellsand, on the lower side, T/C expressed as % as to the effect of thecompound A as compared with the untreated case.

FIG. 2 shows the integrin expression inhibitory action of the compound A(0.05 μg/ml) on a human colonic cancer cell line (HCT116-C9) after 48hours: the effect of the compounds A as compared with the untreated caseis expressed as T/C (%).

FIG. 3 shows the integrin expression inhibitory action of the compound Awith a high concentration (0.5 μg/ml and 5 μg/ml) on a human normalfibroblast cell line (WI38) after 48 hours: the effect of the compoundsA as compared with the untreated case is expressed as T/C (%).

FIG. 4 shows the integrin α2 expression inhibitory action of eachcompound (0.5 μg/ml) on human umbilical cord endothelial cells (HUVEC)after 48 hours: the rate of the quantity of integrin α2 expressed ascompared with the untreated case is expressed as (%). (The name of eachcompound is shown by Synthetic Example number.)

The effect of the compound of the present invention will be shown belowby way of examples of pharmacological experiments.

It is to be noted that the compound A in the examples of pharmacologicalexperiments indicates the compound obtained in Synthetic Example 1.

EXAMPLE 1 Integrin Expression Inhibitory Action on a Human UmbilicalVenous Endothelial Cells (HUVEC)

Human umbilical venous endothelial cells (HUVEC) of 5×10⁵ in number wereseeded in a 75 cm² cell culture bottle and then cultured using an EGMmedium (Sanko Junyaku) at 37° C. in a CO₂ incubator. Then, after 3hours, the EGM medium was exchanged for the same medium includingcompound A, which was then cultured for further 48 hours. Next, thecells were collected and washed with a bovine serum albumin-containingphosphate buffer solution and the above buffer solution containingvarious anti-human integrin mouse antibodies was added to the cells andthe solution containing cells was allowed to stand at 4° C. for 30minutes. After washed, FITC connective anti-mouse IgG antibody was addedto the cells, which was then allowed to stand for 30 minutes and washedagain. Next, the cells were fixed and the amount of antibody connectedper cell was measured as the amount of FITC by using a flow cytometer.

As shown in FIG. 1 described later, the compound A inhibited theexpression of integrins α2, α3, α5, α6, αv, β1, β3 and β5 on the surfaceof the cell in a concentration of 0.05 μg/ml.

EXAMPLE 2 Integrin Expression Inhibitory Action on a Human ColonicCancer Cell Line (HCT116-C9)

The integrin expression inhibitory action of the compound A on the abovecells was examined in the same manner as in Example 1.

As shown in FIG. 2 described later, the compound A inhibited theexpression of integrins α2, α3, α5, α6, β1 and β4 in a concentration of0.05 μg/ml and in a concentration of 0.5 μg/ml.

EXAMPLE 3 Integrin Expression Inhibitory Action on a Human NormalFibroblast Cell Line (WI38)

The integrin expression inhibitory action of the compound A on the abovecells was examined in the same manner as in Example 1.

As shown in FIG. 3 described later, the compound A having a higherconcentration than in Examples 1 and 2 slightly inhibited the expressionof integrins α2, α3 and α4, but had no influence on the expression ofintegrins α1, α5, α6 and β1.

As mentioned above, it is clear that the compound A inhibits theexpression of integrin in endothelial cells and cancer cells but exertsalmost no inhibitory action on normal fibroblast cells.

EXAMPLE 4 Antiangiogenic Effect-1

The inhibition degree of angiogenesis which was observed when aortapieces of rat were incubated in collagen was defined as anantiangiogenic effect. That is, the aorta excised from male rat ofSprague-Dawley strain (10-12 weeks age) was washed with a Hanks'solution so that fat tissues around there were removed minutely. Theaorta was incised to prepare pieces of 2 mm square and they were allowedto stand in a 24-well plate holding the endothelial cells upside. Then,500 μl of neutralized Type I collagen (Cell Matrix Type I-A;manufactured by Nitta Gelatin) were poured over each well and allowed tostand at room temperature for about 20 minutes in a clean bench tosolidify the gel. After confirming that the gel was solidified, 500 μlof MCDB 131 medium (manufactured by Chlorella Kogyo) were added theretofollowed by incubating in a CO₂ incubator (5% CO₂) at 37° C. On the nextday, the culture medium was exchanged with 500 μl of MCDB 131 mediumcontaining the test compound and the incubation was continued. Afterthree days, the medium was again exchanged with 500 μl of MCDB 131medium containing the test compound and, at the stage of the 7th dayfrom the initiation of addition of the test compound, numbers ofcapillaries formed around the aorta were counted under a microscope. Thesolution containing the test compound was prepared in a three-folddilution system where 10 μg/ml was the highest concentration.

Inhibiting rate was calculated from the following formula and 50%inhibiting concentration (IC₅₀) for each test compound was determined.

Inhibiting Rate(%)=(C−T)/C×100

C: Numbers of capillaries when no compound was added

T: Numbers of capillaries when a compound was added

The compound according to the present invention showed an IC₅₀ value of0.05 to 3 μg/ml.

EXAMPLE 5 Antiangiogenic Effect-2

0.4 ml of type I collagen was added to a 24-well plate and solidified.Human umbilical venous endothelial cells (HUVEC) of 8×10⁴ in number wereseeded on the collagen and cultured overnight by using endothelial cellsculture solution (Gibco BRL) containing 10 ng/ml EGF and 20 ng/ml bFGF.Next, the supernatant was removed and then 0.4 ml of the same collagenwas overlaid. A culture solution containing 1.5 ml of the compound A wasfurther added and the cells were cultured for 4 days. Thereafter, thearea of the formed tube was measured quantitatively by image analysis.

The IC₅₀ of the compound A was 0.12 μg/ml. It was confirmed that an α2antibody had the same effect, but this effect was not observed in thecase of an α5 antibody.

EXAMPLE 6 Antiangiogenic Effect-3 (In Vivo)

The above activity was evaluated using a method obtained by improving amouse air capsule method (Sakamoto et al., Cancer Res., 1, 55-57, 1986)in part. Specifically, a millipore ring (Nippon Millipore) was sealedusing a 0.22 μm membrane filter (HAWPO, Nippon Millipore) to form achamber. 1×10⁷ human colic cancer cell strains (WiDr) which weresuspended in a phosphoric acid buffer solution were sealed into thechamber. Next, an air capsule was formed on a subcutaneous site of thebackside of a C57 Black female mouse of 6 to 8 weeks age and theforegoing chamber was transplanted to the air capsule. The compound Awas orally administered after about 6 hours passed after thetransplantation was finished and afterwards administered in sequenceonce a day for 3 days. The erythrocytes of the mouse that was labeledwith ⁵¹Cr was injected from the tail vein 4 days after the chamber wastransplanted. After one hour, the skin at the portion which was incontact with the chamber was resected under anesthesia. After the skinwas frozen, only the portion which was in contact with the chamber wasseparated precisely to measure the amount of blood by using a γcounter.Then, a value obtained by subtracting the amount of blood measured inthe case of the chamber including no cancer cell from the above amountof blood was determined as the amount of angiogenesis. In theexperiment, the control groups consisted of 10 mice per group and thecompound-administrated groups consisted of 5 mice per group.

If the results are evaluated by T/C (%): the amount of angiogenesis ofthe compound-administered groups/the amount of angiogenesis of thevehicle-administered groups×100, the compound A had such an effect asT/C=53% at a dose of 50 mg/kg.

EXAMPLE 7 Integrin α2 Expression Inhibitory Action on a Human UmbilicalVenous Endothelial Cells (HUVEC)

Human umbilical venous endothelial cells (HUVEC) of 5×10⁵ in number wereseeded in a 75 cm² cell culture bottle and then cultured using an EGMmedium (Sanko Junyaku) at 37° C. in a CO₂ incubator. Then, after 3hours, the EGM medium was exchanged for the same medium including acompound of 0.5 μg/ml, which was then cultured for further 48 hours.Next, the cells were collected and washed with a bovine serumalbumin-containing phosphate buffer solution and the above buffersolution containing an anti-human integrin α2 mouse antibody was addedthereto and the solution was allowed to stand at 4° C. for 30 minutes.After washed, FITC connective anti-mouse IgG antibody was added to thecells, which was then allowed to stand for 30 minutes and washed again.Next, the cells were fixed and the amount of antibody connected per cellwas measured as the amount of FITC by using a flow cytometer. Theinhibitory action of each compound is shown by the ratio (%) of theamount of expression to that obtained in the untreated compound. Thename of each compound is shown by Synthetic Example number.

As shown in FIG. 4 described later, each compound inhibited theexpression of integrin α2 on the surface of the cell in a concentrationof 0.5 μg/ml.

Compounds according to the present invention are disclosed concretely inJP-A 7-165708 and JP-A 8-231505. Further, Production Examples andSynthetic Examples of typical compounds of the compound of the presentinvention will be given hereinbelow. It is needless to say that thepresent invention is not limited only to these Examples.

PRODUCTION EXAMPLE 1 Ethyl pyruvate N-(5-methyl-2-nitrophenyl)hydrazone

75.0 g (493 mmol) of 5-methyl-2-nitroaniline was added to a mixedsolution of 160 ml of water and 170 ml of concentrated hydrochloric acidand the mixture was stirred. To the mixture was added dropwise 80 ml ofan aqueous solution containing 36.0 g (517 mmol) of sodium nitrite at−20° C. The reaction solution was added to a solution obtained bydissolving ethyl 2-methylacetoacetate in 100 ml of ethanol and thenadding 200 ml of a 12N aqueous potassium hydroxide thereto, at −20° C.over 30 minutes under stirring. After stirring at the same temperaturefor 30 minutes, 100 ml of concentrated hydrochloric acid was addedthereto. The resulting precipitates were collected by filtration, washedwith water and dried under reduced pressure overnight. A mixed solutionof diethyl ether and hexane was added thereto and the crystals werecollected by filtration, to give 130 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.29 (3H, t, J=7.2 Hz), 2.16 (3H, s), 2.40 (3H,s), 4.25 (2H, q, J=7.2 Hz), 6.91 (1H, dd, J=8.8, 2.0 Hz), 7.63 (1H, s),8.07 (1H, d, J=8.8 Hz), 10.69 (1H, s)

PRODUCTION EXAMPLE 2 Ethyl 4-methyl-7-nitro-1H-indole-2-carboxylate

To a xylene suspension (250 ml) of 25.0 g (94.2 mmol) of the compound ofProduction Example 1 was added 100 g of polyphosphoric acid, followed byheating under reflux for 3 hours. Under ice-cooling, to the reactionmixture were added 80 ml of water and 300 ml of ethyl acetate. Theinsoluble matters were filtered off and washed with 1.5 l of ethylacetate, and the filtrate was extracted with ethyl acetate. The organiclayer was successively washed with an aqueous saturated sodiumbicarbonate, water and brine, dried over magnesium sulfate andconcentrated to dryness. To the residue was added a mixed solution oftert-butyl methyl ether and hexane, and the crystals were collected byfiltration, to give 11.1 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.35 (3H, t, J=7.2 Hz), 2.65 (3H, s), 4.38 (2H,q, J=7.2 Hz), 7.16 (1H, d, J=8.4 Hz), 7.51 (1H, s), 8.19 (1H, d, J=8.4Hz), 11.29 (1H, br s)

PRODUCTION EXAMPLE 3 4-Methyl-7-nitro-1H-indole-2-carboxylic acid

150 ml of a 1 N aqueous sodium hydroxide was added to a tetrahydrofuransolution (150 ml) containing 11.0 g (44.3 mmol) of the compound ofProduction Example 2, followed by heating under stirring at 80° C. for30 minutes. The reaction solution was concentrated and 40 ml of 5Nhydrochloric acid was added to the residue under ice-cooling to adjustthe solution to pH 1. The resulting precipitates were collected byfiltration and washed with water. The precipitates were dissolved in 300ml of tetrahydrofuran, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, dried over magnesium sulfateand concentrated to dryness, to give 9.60 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.62 (3H, s), 7.13 (1H, d, J=8.0 Hz), 7.42 (1H,s), 8.15 (1H, d, J=8.0 Hz), 11.00 (1H, br s)

PRODUCTION EXAMPLE 4 4-Methyl-7-nitro-1H-indole

9.58 g (43.5 mmol) of the compound of Production Example 3 was dissolvedin 60 ml of 1,3-dimethyl-2-imidazolidinone. To the mixture was added1.04 g (4.35 mmol) of basic copper carbonate, followed by heating understirring at 180° C. for 4 hours. 120 ml of ethyl acetate was added tothe reaction solution under ice-cooling, the insoluble matters werefiltered off, and the filtrate was extracted with ethyl acetate. Theorganic layer was successively washed with water and brine, dried overmagnesium sulfate and concentrated. Then, the residue was purified bysilica gel column chromatography, to give 4.87 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.59 (3H, s), 6.74 (1H, s), 7.03 (1H, d, J=8.4Hz), 7.48 (1H, s), 8.00 (1H, d, J=8.4 Hz), 11.86 (1H, br s)

PRODUCTION EXAMPLE 5 3-Formyl-4-methyl-7-nitro-1H-indole

1.5 ml (16.1 mmol) of phosphorous oxychloride was added to 12 ml (154mmol) of dimethylformamide at 0° C. in nitrogen atmosphere, followed bystirring at the same temperature for 20.5 hours. A dimethylformamidesolution (20 ml) containing 2.0 g (11.4 mmol) of the compound ofProduction Example 4 was added thereto at 0° C., followed by heatingunder stirring at 90° C. for 21 hours. 100 ml of a 1N aqueous sodiumhydroxide was added to the reaction solution under ice-cooling, and themixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and brine, dried over magnesium sulfateand concentrated to dryness. A mixed solution of tert-butyl methyl etherand hexane was added to the residue, and the crystals were collected byfiltration, to give 2.23 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.90 (3H, s), 7.21 (1H, d, J=8.4 Hz), 8.11 (1H,d, J=8.4 Hz), 8.39 (1H, s), 10.01 (1H, s), 12.71 (1H, br s)

PRODUCTION EXAMPLE 6 3-Cyano-4-methyl-7-nitro-1H-indole

2.21 g (10.8 mmol) of the compound of Production Example 5 was dissolvedin 100 ml of dimethylformamide, followed by adding 900 mg (13.0 mmol) ofhydroxylamine hydrochloride and 1.05 ml (13.0 mmol) of pyridine. Afterheating under stirring at 60° C. for 40 minutes, 1,1-carbonyldiimidazole(53.9 mmol) was added to the reaction solution under ice-cooling. Afterheating under stirring at 60° C. for further 30 minutes, 3.0 ml (21.5mmol) of triethylamine was added to the reaction solution and themixture was heated under stirring at the same temperature for furtherone hour. 50 ml of ice-water was added to the reaction mixture solutionunder ice-cooling, and the mixture was extracted with ethyl acetate. Theorganic layer was successively washed with water and brine, dried overmagnesium sulfate and concentrated to dryness. A mixed solution oftert-butyl methyl ether and hexane was added to the residue and thecrystals were collected by filtration, to give 1.95 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.78 (3H, s), 7.22 (1H, d, J=8.0 Hz), 8.14 (1H,d, J=8.0 Hz), 8.41 (1H, s), 12.76 (1H, br s)

PRODUCTION EXAMPLE 7 7-Bromo-4-methyl-1H-indole

1 l (1 mol) of a tetrahydrofuran solution containing 1.0 Mvinylmagnesium bromide was added to a tetrahydrofuran solution (300 ml)containing 65.0 g (301 mmol) of 2-bromo-5-methylnitrobenzene at −60° C.under stirring for one hour in nitrogen atmosphere. An aqueous saturatedammonium chloride and ethyl acetate were added to the reaction mixturesolution, and the insoluble matters were filtered off. The filtrate wasdried over magnesium sulfate and concentrated. Then, the residue waspurified by silica gel column chromatography, to give 35.5 g of thetitle compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.42 (3H, s), 6.55 (1H, s), 6.73 (1H, d, J=7.6Hz), 7.16 (1H, d, J=7.6 Hz), 7.35 (1H, s), 11.24 (1H, br s)

PRODUCTION EXAMPLE 8 4-Methyl-1H-indole-7-carboxylic acid

240 ml (384 mmol) of a hexane solution containing 1.6 M butyl lithiumwas added to a tetrahydrofuran solution (200 ml) containing 35.5 g (169mmol) of the compound of Production Example 7 at −78° C. under stirringin nitrogen atmosphere. After stirring under ice-cooling for 40 minutes,carbon dioxide was passed through the reaction solution at −50° C. andthe mixture was stirred as it was for 15 minutes. Water was added to thereaction mixture solution at the same temperature and the solvent wasevaporated. The resulting precipitates were collected by filtration andwashed with water. The precipitates was dissolved in 300 ml oftetrahydrofuran, dried over magnesium sulfate and concentrated todryness, to give 25.9 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.51 (3H, s), 6.53 (1H, s), 6.88 (1H, d, J=7.6Hz), 7.31 (1H, s), 7.62 (1H, d, J=7.6 Hz), 10.99 (1H, br s), 12.79 (1H,br s)

PRODUCTION EXAMPLE 9 7-(N-tert-Butoxycarbonyl)amino-4-methyl-1H-indole

7.0 g (40.0 mmol) of the compound of Production Example 8 was suspendedin 80 ml of toluene, 22 ml (160 mmol) of triethylamine and 11.2 ml (52mmol) of diphenylphosphorylazide were added to the mixture in nitrogenatmosphere, and the mixture was stirred at room temperature for 30minutes. 8 ml (84 mmol) of tert-butanol was added to the reactionsolution, followed by heating under stirring at 100° C. for 2.5 hours.Then, the reaction solution was concentrated, and the residue wasdissolved in ethyl acetate. The mixture was successively washed with 0.1N hydrochloric acid, water and brine, dried over magnesium sulfate andconcentrated to dryness. A mixed solution of diethyl ether and hexanewas added to the residue and the crystals were collected by filtration,to give 7.87 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.48 (9H, s), 2.38 (3H, s), 6.37-6.44 (1H, m),6.68 (1H, d, J=8.4 Hz), 7.22-7.31 (2H, m), 8.86 (1H, br s), 10.73 (1H,br s)

PRODUCTION EXAMPLE 107-(N-tert-Butoxycarbonyl)amino-3-formyl-4-methyl-1H-indole

40 ml (429 mmol) of phosphorous oxychloride was added to 400 ml (5.2mol) of dimethylformamide at 0° C. in nitrogen atmosphere, followed bystirring at the same temperature for 25 minutes. 74.0 g (300 mmol) ofthe compound of Production Example 9 was added thereto at 0° C.,followed by stirring at room temperature for 1.5 hours. The reactionmixture was adjusted to pH 8 by adding 250 ml of a 5N aqueous sodiumhydroxide thereto under ice-cooling. The organic layer was separated byadding tetrahydrofuran, ethyl acetate and water thereto. It wassuccessively washed with water and brine, and dried over magnesiumsulfate. Then, the solvent was evaporated, a mixed solution of diethylether and hexane was added to the residue, and the crystals werecollected by filtration, to give 53.7 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.50 (9H, s), 2.71 (3H, s), 6.90 (1H, d, J=7.6Hz), 7.32-7.41 (1H, m), 8.21 (1H, d, J=1.6 Hz), 8.99 (1H, br s), 9.93(1H, s), 11.88 (1H, br s)

PRODUCTION EXAMPLE 117-(N-tert-Butoxycarbonyl)amino-3-cyano-4-methyl-1H-indole

4.43 g (16.2 mmol) of the compound of Production Example 10 wasdissolved in 50 ml of dimethylformamide, followed by adding 1.35 g (19.4mmol) of hydroxylamine hydrochloride and 1.6 ml (19.8 mmol) of pyridinethereto. After heating under stirring at 60° C. for 45 minutes,1,1-carbonyldiimidazole (80.8 mmol) was added to the reaction solutionunder ice-cooling. After heating under stirring at 60° C. for further 30minutes, 4.5 ml (32.3 mmol) of triethylamine was added to the reactionsolution, and the mixture was heated under stirring at the sametemperature for further 30 minutes. Water was added to the reactionmixture solution under ice-cooling, and the mixture was extracted withethyl acetate. The organic layer was successively washed with water andbrine, dried over magnesium sulfate and then concentrated to dryness, togive 4.27 of the target compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.49 (9H, s), 2.60 (3H, s), 6.89 (1H, d, J=8.0Hz), 7.34-7.42 (1H, m), 8.20 (1H, d, J=2.8 Hz), 9.04 (1H, br s), 11.80(1H, br s)

PRODUCTION EXAMPLE 12 7-Amino-3-cyano-4-methyl-1H-indole

12.6 g (62.6 mmol) of the compound of Production Example 6 was dissolvedin a mixed solution of 100 ml of tetrahydrofuran and 100 ml of methanol,and the mixture was hydrogenated at an ordinary temperature under 3atoms in the presence of 430 mg (1.87 mmol) of platinum oxide. Thecatalyst was filtered off and the filtrate was concentrated to dryness.Then, a mixed solution of tert-butyl methyl ether and hexane was addedto the residue and the crystals were collected by filtration, to give10.7 g of the title compound. 50.5 g (186 mmol) of the compound ofProduction Example 11 was dissolved in 400 ml of dichloromethane. Innitrogen atmosphere, 210 ml (2.76 mol) of trifluoroacetic acid was addedthereto at 0° C., followed by stirring at room temperature for 40minutes. The reaction mixture was adjusted to pH 7 by adding a 5Naqueous sodium hydroxide thereto. The solvent was removed, and then theresidue was extracted with ethyl acetate. The organic layer wassuccessively washed with water and brine, dried over magnesium sulfateand concentrated to dryness. A mixed solution of diethyl ether andhexane was added to the residue and the crystals were collected byfiltration, to give 24.5 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.47 (3H, s), 5.07 (2H, s), 6.34 (1H, d, J=7.6Hz), 6.64 (1H, d, J=7.6 Hz), 8.10 (1H, s), 11.70 (1H, br s)

PRODUCTION EXAMPLE 13 3-Cyanobenzenesulfonyl chloride

25.0 g (212 mmol) of 3-cyanoaniline was added to a mixed solution of 200ml of water and 250 ml of concentrated hydrochloric acid and the mixturewas stirred. An aqueous solution (80 ml) containing 15.5 g (223 mmol) ofsodium nitrite was added dropwise into the mixture at −10° C. Thereaction solution was added to a sulfur dioxide saturated acetic acidsolution (solution prepared by saturating 250 ml of acetic acid withsulfur dioxide and then adding 2.1 g of cuprous chloride thereto) underice-cooling with stirring. After one hour, the reaction solution waspoured into 500 ml of ice-water and extracted with diethyl ether. Theextract was successively washed with an aqueous saturated sodiumbicarbonate, water and brine, and dried over magnesium sulfate. Thesolvent was evaporated, and to the residue was added a mixed solution ofdiethyl ether and hexane. The crystals were collected by filtration, togive 16.0 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 7.55 (1H, t, J=8.0 Hz), 7.78 (1H, dd, J=8.0,1.2 Hz), 7.86-7.92 (2H, m)

PRODUCTION EXAMPLE 14 4-Sulfamoylbenzenesulfonyl chloride

25.0 g (145 mmol) of 4-aminobenzenesulfonamide was added to a mixedsolution of 80 ml of water and 50 ml of concentrated hydrochloric acid,followed by stirring. To the mixture was added dropwise an aqueoussolution (20 ml) containing 10.5 g (152 mmol) of sodium nitrite at −13°C. to −10° C. over 15 minutes. After 10 minutes, the reaction solutionwas added to a sulfur dioxide saturated mixture solution (solutionprepared by saturating a mixed solution of 150 ml of acetic acid and12.5 ml of concentrated hydrochloric acid with sulfur dioxide and thenadding 3.7 g of cuprous chloride thereto) at −30° C. under stirring.After one hour, 500 ml of ice-water was added to the reaction solution,and the precipitates were collected by filtration. The precipitates weredissolved in a mixed solution of 450 ml of toluene and 150 ml of ethylacetate. After filtering off the insoluble matters, the filtrate wasextracted with ethyl acetate. The organic layer was successively washedwith an aqueous saturated sodium bicarbonate and brine, and dried overmagnesium sulfate. The solvent was evaporated, and 100 ml of toluene wasadded to the residue. The crystals were collected by filtration, to give20.9 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 7.65-7.69 (2H, m), 7.71-7.78 (4H, m)

PRODUCTION EXAMPLE 15 5-Bromo-3-chloro-7-nitro-1H-indole

1.4 ml of dimethylformamide and 6.98 g (52.3 mmol) ofN-chlorosuccinimide were added to a tetrahydrofuran solution (140 ml)containing 12.00 g (49.8 mmol) of 5-bromo-7-nitro-1H-indole, followed bystirring at room temperature overnight. An aqueous 10% sodiumthiosulfate was added thereto, followed by extracting with ethylacetate. The organic layer was successively washed with water and brine,dried over magnesium sulfate and concentrated to dryness, to give 14.84g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 7.79 (1H, s), 8.15 (1H, s), 8.23 (1H, s), 12.32(1H, br s)

PRODUCTION EXAMPLE 16 7-Amino-5-bromo-3-chloro-1H-indole hydrochloride

70 ml of concentrated hydrochloric acid and 31.97 g (269 mmol) of a tinpowder were added to a methanol solution (250 ml) containing 14.84 g(53.9 mmol) of the compound of Production Example 15, and the mixturewas stirred at room temperature for 80 minutes. Under ice-cooling, themixture was adjusted to pH 10 by adding a 5N aqueous sodium hydroxidesolution thereto. Then, the resulting precipitates were filtered off andthe filtrate was extracted with ethyl acetate. The organic layer wassuccessively washed with an aqueous saturated sodium bicarbonate andbrine, dried over magnesium sulfate and concentrated. Then, the residuewas purified by silica gel column chromatography, to give 14.35 g of7-amino-5-bromo-3-chloro-1H-indole. The product was dissolved in ethylacetate, and 17 ml of a 4N aqueous hydrogen chloride-ethyl acetatesolution was added thereto. The resulting precipitates were collected byfiltration and washed with hexane, to give 13.23 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 5.11 (3H, br s), 6.64 (1H, s), 6.93 (1H, s),7.50 (1H, d, J=2.0 Hz), 11.38 (1H, br s)

PRODUCTION EXAMPLE 17 Ethyl pyruvate 2-(4-methyl-2-nitrophenyl)hydrazone

30.00 g (0.197 mol) of 4-methyl-2-nitroaniline was suspended in 110 mlof water, to which was then added 66 ml of concentrated hydrochloricacid. An aqueous solution (35 ml) containing 16.33 g (0.237 mol) ofsodium nitrite was added dropwise to the mixture at 10° C. or less andthe resulting mixture was stirred under ice-cooling for 40 minutes toprepare a diazonium salt solution.

28.43 g (0.197 mol) of ethyl 2-methylacetoacetate was dissolved in amixed solution of 150 ml of ethanol and 300 ml of water. Underice-cooling, an aqueous solution (120 ml) containing 53.36 g (0.808 mol)of potassium hydroxide was added thereto. In succession, the diazoniumsalt solution which was previously prepared was added dropwise thereintoat the same temperature and the resulting mixture was stirred underice-cooling for 20 minutes. The mixture was adjusted to pH 1 by addingconcentrated hydrochloric acid thereto. The resulting precipitates werecollected by filtration, washed with water and dried over phosphorouspentaoxide under reduced pressure, to give 46.42 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.40 (3H, t, J=7.2 Hz), 2.23 (3H, s), 2.36 (3H,s), 4.35 (2H, q, J=7.2 Hz), 7.44 (1H, dd, J=8.8, 1.6 Hz), 7.93 (1H, d,J=8.8 Hz), 8.00 (1H, s), 10.87 (1H, br s)

PRODUCTION EXAMPLE 18 Ethyl 5-methyl-7-nitro-1H-indole-2-carboxylate

65.33 g of polyphosphoric acid was added to a xylene solution (320 ml)containing 15.92 g (60 mmol) of the compound of Production Example 18,followed by heating under reflux overnight. Water and ethyl acetate wereadded thereto, and the insoluble matters were filtered off. The organiclayer was separated, successively washed with water and brine, driedover magnesium sulfate and concentrated. Then, the residue was purifiedby silica gel column chromatography, to give 7.32 g of the titlecompound.

¹-NMR (DMSO-d₆) δ(ppm): 1.34 (3H, t, J=7.0 Hz), 2.47 (3H, s), 4.36 (2H,q, J=7.0 Hz), 7.35 (1H, s), 7.99 (1H, s), 8.11 (1H, s), 11.25 (1H, br s)

PRODUCTION EXAMPLE 19 5-Methyl-7-nitro-1H-indole

150 ml of an aqueous 1 N sodium hydroxide solution was added to atetrahydrofuran solution (80 ml) containing 7.86 g (31.7 mmol) of thecompound of Example 19 and the mixture was stirred at room temperaturefor 3.5 hours. Under ice-cooling, the mixture was adjusted to pH 1 byadding 2N hydrochloric acid and then extracted with ethyl acetate. Theorganic layer was successively washed with water and brine, dried overmagnesium sulfate and concentrated to dryness, to give 7.13 g of5-methyl-7-nitro-1H-indole-2-carboxylic acid. The product was dissolvedin 160 ml of 1,3-dimethyl-2-imidazolidinone, 716 mg (3.24 mmol) of basiccopper carbonate was added thereto, and the mixture was stirred at 185°C. for 2 hours. The reaction solution was poured into water, theinsoluble matters were filtered off and the filtrate was extracted withethyl acetate. The organic layer was successively washed with water andbrine, dried over magnesium sulfate and concentrated. Then, the residuewas purified by silica gel column chromatography, to give 4.50 g of thetitle compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.46 (3H, s), 6.62 (1H, d, J=2.8 Hz), 7.47 (1H,d, J=2.8 Hz), 7.87 (1H, s), 7.92 (1H, s), 11.77 (1H, br s)

PRODUCTION EXAMPLE 20 3-Bromo-5-methyl-7-nitro-1H-indole

0.7 ml of dimethylformamide and 4.78 g of (26.9 mmol) ofN-bromosuccinimide were added to a tetrahydrofuran solution (70 ml)containing 4.50 g (25.5 mmol) of the compound of Production Example 20,followed by stirring at room temperature for 70 minutes. An aqueous 10%sodium thiosulfate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was successively washedwith water and brine, dried over magnesium sulfate and then concentratedto dryness, to give 6.53 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.50 (3H, s), 7.67 (1H, s), 7.73 (1H, s), 8.02(1H, s), 12.10 (1H, br s)

PRODUCTION EXAMPLE 21 7-Amino-3-bromo-5-methyl-1H-indole

6.76 g (26.5 mmol) of the compound of Production Example 20 wassuspended in a mixed solution of 150 ml of methanol and 75 ml of water.To the mixture were added 11.34 g (212 mmol) of ammonium chloride and5.92 g (106 mmol) of an iron powder. After stirring at 80° C. for onehour, the insoluble matters were filtered off and the filtrate wasadjusted to pH 8 by adding an aqueous saturated sodium bicarbonatethereto. The mixture was extracted with ethyl acetate, and the organiclayer was successively washed with an aqueous saturated bicarbonate,water and brine, dried over magnesium sulfate and concentrated. Then,the residue was purified by silica gel column chromatography, to give3.30 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.24 (3H, s), 5.08 (2H, br s), 6.20 (1H, s),6.41 (1H, s), 7.35 (1H, s), 10.86 (1H, br s)

PRODUCTION EXAMPLE 22 6-Amino-3-pyridinesulfonyl chloride

Under ice-cooling, 10.00 g (0.106 mol) of 2-aminopyridine was addedlittle by little to 123.8 g (1.06 mol) of chlorosulfonic acid. To themixture was added 50.56 g (0.425 mol) of thionyl chloride. The mixturewas heated under reflux for 2.5 hours, and further stirred at 150° C.for 7 hours. The reaction solution was poured into ice-water,neutralized by adding sodium bicarbonate and extracted with ethylacetate. The organic layer was successively washed with an aqueoussaturated sodium bicarbonate, water and brine, dried over magnesiumsulfate, and then concentrated to dryness. The residue was suspended inethyl ether and the insoluble matters were filtered off. The filtratewas concentrated to dryness and the residue was recrystallized fromethyl ether/hexane, to give 6.58 g of the title compound.

PRODUCTION EXAMPLE 23 4,7-Dibromo-1H-indole

The title compound (27.2 g) was obtained from 62.0 (0.224 mol) g of2,5-dibromonitrobenzene in the same manner as in the Production Example1 of JP-A 7-165708.

¹H-NMR (DMSO-d₆) δ(ppm): 6.52 (1H, d, J=3.2 Hz), 7.18 (1H, d, J=8.0 Hz),7.26 (1H, d, J=8.0 Hz), 7.53 (1H, d, J=3.2 Hz), 11.75 (1H, br s)

PRODUCTION EXAMPLE 24 7-Amino-4-bromo-1H-indole hydrochloride

Into a tetrahydrofuran solution (300 ml) containing 27.2 g (98.9 mmol)of the compound of Production Example 23 was added dropwise a 186 ml(116.3 mmol) of a hexane solution containing 1.6 M n-butyllithium at−78° C. in a nitrogen atmosphere, followed by stirring under ice-coolingfor one hour. After cooling again to −78° C., 28 ml (0.13 mmol) ofdiphenylphosphrylazide was added dropwise thereinto. The mixture wasstirred at −78° C. for one hour and in succession, at −40° C. for onehour. A toluene solution (150 g) containing 3.4 M sodiumbis(2-methoxyethoxy)aluminum hydride was added thereto at −40° C.,followed by stirring at room temperature for one hour. Water (120 ml)was added thereto, the insoluble matters were collected by filtrationand the filtrate was extracted with ethyl ether. The organic layer wassuccessively washed with an aqueous saturated sodium bicarbonate andbrine, dried over magnesium sulfate and concentrated. Then, the residuewas dissolved in ethyl ether, and 50 ml of a 4 N-hydrochloric acid/ethylacetate solution was added thereto. The resulting precipitates werecollected by filtration, to give 14.5 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.41-6.43 (1H, m), 6.80 (1H, d, J=8.0 Hz), 7.16(1H, d, J=8.0 Hz), 7.54 (1H, t, J=2.8 Hz), 11.57 (1H, br s)

PRODUCTION EXAMPLE 25 7-Bromo-4-chloro-1H-indole

The title compound was obtained in the same manner as in ProductionExample 23.

¹H-NMR (DMSO-d₆) δ(ppm): 6.60-6.61 (1H, m), 7.04 (1H, d, J=8.1 Hz), 7.32(1H, d, J=8.1 Hz), 7.53 (1H, t, J=2.7 Hz), 11.74 (1H, br s)

PRODUCTION EXAMPLE 26 7-Amino-4-chloro-1H-indole hydrochloride

The title compound was obtained in the same manner as in ProductionExample 24.

¹H-NMR (DMSO-d₆) δ(ppm): 6.54-6.55 (1H, m), 7.05 (1H, d, J=8.1 Hz), 7.11(1H, d, J=8.1 Hz), 7.60 (1H, t, J=2.7 Hz), 11.82 (1H, br s)

PRODUCTION EXAMPLE 27 5-Bromo-2-thiophenecarboxyaldehyde

27.0 ml (43.4 mmol) of a hexane solution containing 1.6 M n-butyllithiumwas added dropwise into a tetrahydrofuran solution (80 ml) containing10.0 g (41.3 mmol) of 5-dibromothiophene at −78° C. in a nitrogenatmosphere, followed by stirring for 10 minutes at the same temperature.Then, 3.5 ml (45.5 mmol) of dimethylformamide was added thereto at thesame temperature, followed by stirring for 20 minutes. Water was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was successively washed with an aqueous 0.1 N hydrochloric acidsolution, water and brine, dried over magnesium sulfate and concentratedto dryness, to give 6.4 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 7.49 (1H, d, J=4.0 Hz), 7.87 (1H, d, J=3.9 Hz),9.81 (1H, s)

PRODUCTION EXAMPLE 28 5-Bromo-2-thiophenecarbonitrile

3.3 g (51.7 mmol) of hydroxylamine hydrochloride and 4.1 g (51.7 mmol)of pyridine were added to a dimethylformamide solution (40 ml)containing 8.2 g (43.1 mmol) of the compound of Production Example 28and the mixture was stirred at room temperature for 30 minutes. Then,34.9 g (215.5 mmol) of 1,1′-carbonyldiimidazole was added underice-cooling and the resulting mixture was stirred at room temperaturefor one hour. Ice-water was added to the reaction solution, and themixture was extracted with ethyl acetate. The organic layer wassuccessively washed with an aqueous 0.1 N hydrochloric acid, water andbrine, dried over magnesium sulfate and concentrated. Then, the residuewas purified by silica gel chromatography, to give 6.7 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 7.45 (1H, d, J=4.0 Hz), 7.84 (1H, d, J=4.0 Hz)

PRODUCTION EXAMPLE 29 5-Benzylthio-2-thiophenecarbonitrile

585 mg (13.4 mmol, oily component: 55%) of sodium hydride was suspendedin 10 ml of dimethyl sulfoxide, 1.4 g (11.2 mmol) of benzylmercaptan wasadded thereto, and the mixture was stirred for 10 minutes. Then, 2.1 g(11.2 mmol) of the compound of Production Example 14 was added, followedby stirring at room temperature for one hour. Water was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theorganic layer was successively washed with water and brine, dried overmagnesium sulfate and concentrated. Then, the residue was purified bysilica gel chromatography, to give 1.51 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 4.26 (2H, s), 7.18 (1H, d, J=4.0 Hz), 7.27-7.30(5H, m), 7.83 (1H, d, J=4.0 Hz)

PRODUCTION EXAMPLE 30 4-Bromo-1H-indolecarboxylic acid

34 g of the title compound was obtained from 51 g of the compound ofProduction Example 23 in the same manner as in Production Example 8.

¹H-NMR (CDCl₃) δ(ppm): 6.51-6.52 (1H, m), 7.35 (1H, d, J=8.0 Hz), 7.48(1H, t, J=2.8 Hz), 7.66 (1H, d, J=8 Hz), 11.4 (1H, br s), 13.2 (1H, brs)

PRODUCTION EXAMPLE 31 7-(N-tert-Butoxycarbonyl)amino-4-bromo-1H-indole

32 g of the title compound was obtained from 34 g of the compound ofProduction Example 30 in the same manner as in Production Example 9.

¹H-NMR (CDCl₃) δ(ppm): 1.51 (9H, s), 6.38-6.39 (1H, m), 7.13 (1H, d,J=8.0 Hz), 7.44-7.46 (2H, m), 9.11 (1H, br s), 11.2 (1H, br s)

PRODUCTION EXAMPLE 327-(N-tert-Butoxycarbonyl)amino-4-bromo-3-chloro-1H-indole

N-Chlorosuccinimide was treated in a tetrahydrofuran-dimethylformamidesolution containing the compound of Production Example 31, to give thetitle compound.

¹H-NMR (CDCl₃) δ(ppm): 1.50 (9H, s), 7.19 (1H, d, J=8.4 Hz), 7.45 (1H,d, J=8.4 Hz), 7.62 (1H, d, J=2.8 Hz), 9.08 (1H, br s), 11.41 (1H, br s)

PRODUCTION EXAMPLE 33 7-Amino-4-bromo-3-chloro-1H-indole hydrochloride

10.87 (31.5 mmol) of the compound of Production Example 32 was dissolvedin methanol (120 ml). To the mixture was added concentrated hydrochloricacid (20 ml), followed by stirring at 60° C. for 40 minutes. After thereaction was finished, the solvent was removed, and the mixture wassubjected to azeotropic distillation for 3 times using ethanol. Theresulting solid was washed with ether, to give 8.5 g of the titlecompound.

¹H-NMR (CDCl₃) δ(ppm): 6.67 (1H, d, J=8.0 Hz), 7.13 (1H, d, J=8.0 Hz),7.65 (1H, d, J=2.8 Hz), 11.74 (1H, br s)

PRODUCTION EXAMPLE 34 2-Amino-5-pyrimidinesulfonyl chloride

21 ml (0.316 mol) of chlorosulfonic acid was cooled in ice-water and 3 g(0.032 mol) of 2-aminopyrimidine was added thereto little by littleunder stirring. 9.2 ml (0.126 mol) of thionyl chloride was further addedthereto, followed by stirring at 150° C. for 70 hours. The reactionsolution was returned to room temperature, poured into water andextracted with ethyl acetate. The extract was dried over sodium sulfateand then concentrated to dryness, to give 1.7 g of the title compound.

¹H-NMR (CDCl₃) δ(ppm): 5.97 (2H, broad), 8.83 (2H, s)

SYNTHETIC EXAMPLE 1N-(3-Cyano-4-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide

2.00 g (11.7 mmol) of the compound of Production Example 12 wasdissolved in 60 ml of tetrahydrofuran, followed by adding 4.0 ml (49.5mmol) of pyridine and 2.60 g (12.9 mmol) of the compound of ProductionExample 13 thereto. After stirring at room temperature for 16 hours, themixture was adjusted to pH 1 to 2 by adding 2 N hydrochloric acid andextracted with ethyl acetate. The organic layer was successively washedwith water and brine, dried over magnesium sulfate and concentrated.Then, the residue was purified by silica gel chromatography, to give3.90 g of the title compound. (The compound hereinafter is referred toas Compound A.)

Melting point: 220-221° C. (recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.55 (3H, s), 6.50 (1H, d, J=8.0 Hz), 6.77 (1H,d, J=8.0 Hz), 7.71 (1H, t, J=8.0 Hz), 7.90 (1H, d, J=8.0 Hz), 8.05-8.13(2H, m), 8.16 (1H, s), 10.11 (1H, br s), 12.01 (1H, br s)

SYNTHETIC EXAMPLE 2N-(3-Cyano-4-methyl-1H-indole-7-yl)-6-chloro-3-pyridinesulfonamide

700 mg (4.09 mmol) of the compound of Production Example 12 wasdissolved in 20 ml of tetrahydrofuran, followed by adding 1.3 ml (16.1mmol) of pyridine and 950 mg (4.48 mmol) of 6-chloro-3-pyridinesulfonylchloride thereto. After stirring at room temperature for 2 hours, thereaction solution was adjusted to pH 1 to 2 by adding 1 N hydrochloricacid and extracted with ethyl acetate. The organic layer wassuccessively washed with water and brine, dried over magnesium sulfateand concentrated. Then, the residue was purified by silica gel columnchromatography, to give 1.16 g of the title compound.

Melting point: 262 to 263° C. (recrystallized from ethanol/n-hexane).

¹H-NMR (DMSO-d₆) δ(ppm): 2.57 (3H, s), 6.55 (1H, d, J=7.6 Hz), 6.82 (1H,d, J=7.6 Hz), 7.69 (1H, d, J=8.4 Hz), 8.01 (1H, dd, J=8.4, 2.4 Hz), 8.17(1H, d, J=2.8 Hz), 8.60 (1H, d, J=2.4 Hz), 10.21 (1H, br s), 12.03 (1H,br s)

SYNTHETIC EXAMPLE 3N-(3-Bromo-5-methyl-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide

200 mg (0.89 mmol) of the compound of Production Example 22 wasdissolved in 6 ml of tetrahydrofuran, followed by adding 0.3 ml (3.71mmol) of pyridine and 300 mg (1.17 mmol) of the compound of ProductionExample 14 thereto. After stirring at room temperature for 48 hours, themixture was adjusted to pH 1 to 2 by adding 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was successively washedwith water and brine, dried over magnesium sulfate and concentrated.Then, a mixed solution of diethyl ether and hexane was added to theresidue and the resulting crystals were collected by filtration, to give387 mg of the title compound.

Melting point: 196-197° C. (recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.24 (3H, s), 6.60 (1H, s), 6.98 (1H, s), 7.44(1H, s), 7.55 (2H, br s), 7.85-7.95 (4H, m), 10.13 (1H, br s), 11.01(1H, br s)

SYNTHETIC EXAMPLE 4N-(5-Bromo-3-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide

1.00 g (3.55 mmol) of the compound of Production Example 16 wassuspended in 25 ml of tetrahydrofuran, followed by adding 0.86 ml (10.6mmol) of pyridine and 718 mg (3.73 mmol) of the compound of ProductionExample 8 thereto under ice-cooling. After stirring at room temperaturefor 3 hours, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was successively washed with water andbrine, dried over magnesium sulfate and concentrated. Then, the residuewas purified by silica gel column chromatography, to give 1.27 g of thetitle compound.

Melting point: started coloring from a temperature close to 237° C. anddecomposed at 240 to 242° C. (recrystallized from ethanol-water)

¹H-NMR (DMSO-d₆) δ(ppm): 6.37 (1H, d, J=8.8 Hz), 6.94 (2H, br s), 6.97(1H, s), 7.36 (1H, s), 7.54-7.57 (2H, m), 8.16 (1H, d, J=2.8 Hz), 9.94(1H, br s), 11.17 (1H, br s)

Hydrochloride

¹H-NMR (DMSO-d₆) δ(ppm): 6.59 (1H, d, J=9.2 Hz), 7.00 (1H, s), 7.40 (1H,s), 7.56 (1H, d, J=2.4 Hz), 7.70 (1H, dd, J=9.2, 2.0 Hz), 8.20 (1H, d,J=2.0 Hz), 10.20 (1H, br s), 11.37 (1H, br s)

SYNTHETIC EXAMPLE 5N-(3-Bromo-5-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide

Under ice-cooling, 0.19 ml (2.35 mmol) of pyridine and 280 mg (1.39mmol) of 3-cyanobenzenesulfonyl chloride were added to a tetrahydrofuransolution (6 ml) containing 260 mg (1.16 mmol) of the compound ofProduction Example 22, followed by stirring at room temperatureovernight. Then, 0.2 N hydrochloric acid was added thereto and themixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and brine, dried over magnesium sulfateand concentrated. Then, the residue was purified by silica gel columnchromatography, to give 360 mg of the title compound.

Melting point: started decomposing gradually from a temperature close to148° C. and decomposed rapidly at 163 to 164° C. (recrystallized fromethanol/n-hexane).

¹H-NMR (DMSO-d₆) δ(ppm): 2.25 (3H, s), 6.54 (1H, s), 7.01 (1H, s), 7.42(1H, d, J=2.8 Hz), 7.71 (1H, t, J=7.6 Hz), 7.93 (1H, d, J=7.6 Hz),8.07-8.11 (2H, m), 10.09 (1H, br s), 11.04 (1H, br s)

SYNTHETIC EXAMPLE 6 N-(4-Bromo-1H-indole-7-yl)-4-cyanobenzenesulfonamide

700 mg (2.8 mmol) of the compound of Production Example 25 and 685 mg(3.4 mmol) of 4-cyanobenzenesulfonyl chloride were processed in the samemanner as in Synthetic Example 1, to give 686 mg of the title compound.

Melting point: 214 to 216° C.

¹H-NMR (DMSO-d₆) δ(ppm): 6.35 (1H, d, J=2.6 Hz), 6.53 (1H, d, J=8.0 Hz),7.04 (1H, d, J=8.0 Hz), 7.41 (1H, t, J=2.8 Hz), 7.85 (2H, d, J=8.0 Hz),8.00 (2H, d, J=8.0 Hz), 10.24 (1H, br s), 11.19 (1H, br s)

SYNTHETIC EXAMPLE 7N-(4-Chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide

1330 mg (6.4 mmol) of the compound of Production Example 23 and 1000 mg(4.9 mmol) of the compound of Production Example 12 were processed inthe same manner as in Synthetic Example 1, to give 961 mg of the titlecompound.

Melting point: 204 to 206° C.

¹H-NMR (DMSO-d₆) δ(ppm): 6.38 (1H, d, J=9.0 Hz), 6.43 (1H, t, J=2.2 Hz),6.77 (1H, d, J=7.7 Hz), 6.86 (2H, br s), 7.42 (1H, t, J=2.6 Hz), 7.56(1H, dd, J=2.6, 9.0 Hz), 8.14 (1H, d, J=2.6 Hz), 9.70 (1H, br s), 11.07(1H, br s)

SYNTHETIC EXAMPLE 8N-(3-Bromo-4-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide and ahydrochloride

1 ml of dimethylformamide and 359 mg (2.0 mmol) of N-bromosuccinimidewere added to a tetrahydrofuran solution (10 ml) containing 650 mg (2.0mmol) of the compound of Synthetic Example 7, followed by stirring atroom temperature overnight. Then, an aqueous 0.2 N hydrochloric acid wasadded thereto, and the mixture was extracted with ethyl acetate. Theorganic layer was successively washed with an aqueous sodiumthiosulfate, water and brine, dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gel columnchromatography, to give 662 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.38 (1H, d, J=8.8 Hz), 6.76 (1H, d, J=8.4 Hz),6.88 (2H, br s), 6.97 (1H, d, =8.4 Hz), 7.52-7.56 (2H, m) 8.12 (1H, d,J=2.4 Hz), 9.68 (1H, br s), 11.44 (1H, br s)

The resulting title compound (660 mg) was dissolved in 3 ml of acetone,followed by adding 0.62 ml of a 4 N-hydrochloric acid/ethyl acetatesolution thereto. The resulting precipitates were collected byfiltration, to give 590 mg of a hydrochloride.

Melting point: started decomposing gradually from a temperature close to267° C.

¹H-NMR (DMSO-d₆) δ(ppm): 6.65 (1H, d, J=9.2 Hz), 6.78 (1H, d, J=8.1 Hz),6.98 (1H, d, J=8.2 Hz), 7.57 (1H, d, =2.6 Hz), 7.73 (1H, dd, J=2.0, 9.0Hz), 8.15 (1H, d, J=2.4 Hz), 10.00 (1H, br s), 11.67 (1H, br s)

SYNTHETIC EXAMPLE 9N-(3-Bromo-5-methyl-1H-indole-7-yl)-5-cyano-2-thiophenesulfonamide

Under ice-cooling, chlorine gas was introduced into a concentratedhydrochloric solution (15 ml) containing 1.3 g (5.6 mmol) of thecompound of Production Example 30. After stirring for 30 minutes, thereaction solution was added to ice-water and extracted with ethylacetate. The organic layer was successively washed with water and brine,dried over magnesium sulfate and concentrated. The residue was added toa pyridine solution (6 ml) containing 1.2 g (5.35 mmol) of the compoundof Production Example 22, followed by stirring at room temperatureovernight. Water was added thereto, and the mixture was extracted withethyl acetate. The organic layer was successively washed with an aqueous1 N hydrochloric acid, water and brine, dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gelchromatography, to give 1227 mg of the title compound.

Melting point: 166 to 169° C. (decomposed)

¹H-NMR (DMSO-d₆) δ(ppm): 2.30 (3H, s), 6.65 (1H, s), 7.07 (1H, s), 7.44(1H, s), 7.54 (1H, d, J=4.0 Hz), 7.94 (1H, d, J=4.0 Hz), 10.47 (1H, brs), 11.04 (1H, br s)

SYNTHETIC EXAMPLE 10N-(4-Bromo-3-chloro-1H-indole-7-yl)-2-amino-5-pyrimidinesulfonamide

513 mg (2.65 mmol) of the compound of Production Example 35 was added to5 ml of a pyridine solution containing 712 mg (2.52 mmol) of thecompound of Production Example 34, followed by stirring for 15 hours.Water was added to the reaction solution, and extracted with a mixedsolution of ethyl acetate and tetrahydrofuran (10:1). The organic layerwas dried over magnesium sulfate and then concentrated. The residue waspurified by silica gel column chromatography, to give 950 mg of thetitle compound.

Melting point: 285 to 289° C.

¹H-NMR (DMSO-d₆) δ(ppm): 6.75 (1H, d, J=8.0 Hz), 7.19 (1H, d, J=8.0 Hz),7.59 (1H, d, J=3.0 Hz), 7.65 (2H, s), 8.37 (2H, s), 9.82 (1H, s), 11.43(1H, s)

SYNTHETIC EXAMPLE 11N-(3-Chloro-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide

767 mg (3.0 mmol) of 4-sulfamoylbenzenesulfonyl chloride was reactedwith 264 mg (2.0 mmol) of 7-amino-1H-indole and treated, to give 445 mgof N-(1H-indole-7-yl)-4-sulfanoylbenzenesulfonamide. The resultingcompound was chlorinated using N-chlorosuccinimide in dichloromethane,to give 349 mg of the title compound.

Melting point: started coloring partially in a black color from atemperature close to 220° C. and decomposed gradually from a temperatureclose to 240° C. (recrystallized from ethanol-n-hexane).

¹H-NMR (DMSO-d₆) δ(ppm): 6.75 (1H, d, J=7.6 Hz), 6.96 (1H, dd, J=8.0,7.6 Hz), 7.29 (1H, d, J=7.6 Hz), 7.50 (1H, d, J=2.8 Hz), 7.58 (2H, s),7.90-7.98 (4H, m), 10.23 (1H, s), 11.07-11.17 (1H, m)

PRODUCTION EXAMPLE 1a 7-Bromo-1H-indole

100 ml (100 mmol) of a tetrahydrofuran solution containing 1.0 Mvinylmagnesium bromide was added to a tetrahydrofuran solution (250 ml)containing 5.05 g (25 mmol) of 2-bromonitrobenzene at −40° C. innitrogen atmosphere, followed by stirring as it was for 40 minutes. Thereaction mixture was poured into 500 ml of an aqueous saturated ammoniumchloride, and the mixture was extracted with ethyl ether. The extractwas dried over magnesium sulfate and concentrated. Then, the residue waspurified by silica gel column chromatography, to give 2.89 g of thetitle compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.56 (1H, dd, J=2.9, 1.8 Hz), 6.94 (1H, t,J=7.8 Hz), 7.30 (1H, d, J=7.8 Hz), 7.40 (1H, t, J=2.9 Hz), 7.56 (1H, d,J=7.8 Hz), 11.16-11.46 (1H, br m)

PRODUCTION EXAMPLE 2a 7-Amino-1H-indole

16.5 ml (41.3 mmol) of a hexane solution containing 2.5 M n-butyllithiumwas added dropwise to a tetrahydrofuran solution (50 ml) containing 2.70g (13.8 mmol) of Production Example 1a at −70° C. in nitrogenatmosphere, and the mixture was stirred at −70° C. for 15 minutes andthen at −20 to −10° C. for 30 minutes. After cooling to −70° C. again,3.9 ml (18 mmol) of diphenylphosphorylazide was added dropwisethereinto. The mixture was stirred at −70° C. for one hour and then at−40° C. for one hour. After adding 22.3 ml (75.8 mmol) of a toluenesolution containing 3.4 M sodium bis(2-methoxyethoxy)aluminum hydridethereto at −40° C., the mixture was stirred at −30 to −20° C. for 30minutes and then at room temperature for 30 minutes. A phosphoric acidbuffer solution having a pH of 7.0 was added thereto, the insolublematters were collected by filtration and the filtrate was extracted withethyl ether. The organic layer was successively washed with an aqueoussaturated sodium bicarbonate and brine, dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gel columnchromatography, to give 1.29 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 5.01 (2H, br s), 6.25-6.33 (2H, m), 6.70 (1H,dd, J=7.9, 7.3 Hz), 6.78 (1H, dd, J=7.9, 0.7 Hz), 7.23 (1H, t, J=2.7Hz), 10.48-10.72 (1H, br m)

The following raw material compounds were synthesized from2-bromonitrobenzene derivatives in the same manner as in ProductionExamples 1a and 2a.

-   7-amino-4-methoxy-1H-indole-   7-amino-4-bromo-1H-indole

PRODUCTION EXAMPLE 3a 7-Bromo-3-chloro-4-methyl-1H-indole

4.0 g (30.0 mmol) of N-chlorosuccinimide was added to an acetonitrilesolution (250 ml) containing 5.8 g (27.6 mmol) of7-bromo-4-methyl-1H-indole synthesized from 2-bromo-5-methylnitrobenzenein the same manner as in Production Example 1a, followed by stirring atroom temperature overnight. 50 ml of a 1N aqueous sodium hydroxide wasadded thereto, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water, dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gel columnchromatography, to give 6.7 g of the title compound.

¹H-NMR (CDCl₃) δ(ppm): 2.74 (3H, s), 6.75-7.26 (3H, m), 8.23 (1H, br s)

PRODUCTION EXAMPLE 4a 7-Amino-3-chloro-4-methyl-1H-indole

2.6 g of the title compound was obtained from 6.37 g (26.1 mmol) of thecompound of Production Example 3a in the same manner as in ProductionExample 2a.

¹H-NMR (CDCl₃) δ(ppm): 2.70 (3H, s), 6.39-7.14 (3H, m), 8.15 (1H, br s)

PRODUCTION EXAMPLE 5a 4-Sulfamoylbenzenesulfonyl chloride

6.4 g (37.2 mmol) of 4-aminobenzenesulfonamide was added to a mixedsolution of 12.5 ml of water and 6.3 ml of concentrated hydrochloricacid, followed by stirring. An aqueous saturated solution containing2.56 g (37.1 mmol) of sodium nitrite was added dropwise thereinto at 0°C. or less. The reaction solution was added to an acetic acid solutionsaturated with sulfur dioxide (solution obtained by saturating 35 ml ofacetic acid with sulfur dioxide and then adding 1.5 g of cupricchloride.dihydrate thereto) under ice-cooling with stirring. After 10minutes, the reaction solution was poured into ice-water, and theprecipitates were collected by filtration and washed with water. Theprecipitates were dissolved in tetrahydrofuran, dried over magnesiumsulfate and then concentrated to dryness, to give 3.5 g of the titlecompound.

PRODUCTION EXAMPLE 6a 4-(Sulfamoylmethyl)benzenesulfonyl chloride

5.0 g (23.1 mmol) of 4-nitrophenylmethanesulfonamide was suspended in90% acetic acid, which was then hydrogenated at normal temperature undernormal pressure in the presence of palladium-carbon. After filtering offthe catalyst, the filtrate was concentrated to dryness, to give 4.3 g of4-aminophenylmethanesulfonamide. The obtained compound was added to amixed solution of 40 ml of water and 4.1 ml of concentrated hydrochloricacid, followed by stirring. An aqueous saturated solution containing1.63 g (23.6 mmol) of sodium nitrite was added dropwise thereinto at 0°C. or less. The reaction solution was added to an acetic acid solutionsaturated with sulfur dioxide (solution obtained by saturating 30 ml ofacetic acid with sulfur dioxide and then adding 0.97 g of cupricchloride.dihydrate thereto) under ice-cooling with stirring. Afterstirring at room temperature for 40 minutes, the reaction solution waspoured into ice-water and the mixture was saturated with sodiumchloride. The mixture was extracted with ethyl acetate, and the extractwas dried over magnesium sulfate and then concentrated to dryness, togive 1.7 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 4.26 (2H, s), 7.32 (2H, d, J=8.4 Hz), 7.59 (2H,d, J=8.4 Hz)

The following compounds were synthesized in the same manner as inProduction Example 5a or 6a.

-   4-(N-methylsulfamoyl)benzenesulfonyl chloride-   4-(N-ethylsulfamoyl)benzenesulfonyl chloride-   4-(N-methoxysulfamoyl)benzenesulfonyl chloride-   4-[(methanesulfonamide)methyl]benzenesulfonyl chloride-   4-(N-methylmethanesulfonamide)benzenesulfonyl chloride-   4-(1-pyrrolidinylsulfonyl)benzenesulfonyl chloride-   4-(1-pyrrolidinylcarbonyl)benzenesulfonyl chloride-   3-cyanobenzenesulfonyl chloride-   4-(methylsulfonyl)benzenesulfonyl chloride-   4-[(N-methylmethanesulfonamide)methyl]benzenesulfonyl chloride

PRODUCTION EXAMPLE 7a 3-Cyano-7-nitro-1H-indole

10.15 g (53.4 mmol) of 3-formyl-7-nitro-1H-indole was dissolved in 150ml of dimethylformamide, and 3.93 g (56.0 mmol) of hydroxylaminehydrochloride and 4.5 ml (55.6 mmol) of pyridine were added thereto.After heating under stirring at 70 to 80° C. for 2 hours, 6.3 g (56.8mmol) of selenium dioxide and about 5 g of magnesium sulfate were addedthereto. After heating at 70 to 80° C. for further 2.5 hours, theinsoluble matters were filtered off and the filtrate was concentrated.Water was added thereto, and the resulting crystals were collected byfiltration and successively washed with water and ethyl ether. Thecrystals were dissolved in a mixed solution of tetrahydrofuran andacetone, and the insoluble matters were filtered off. Afterconcentrating the filtrate, ethyl acetate was added to the residue andthe crystals were collected by filtration, to give 8.61 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 7.48 (1H, t, J=8.1 Hz), 8.17 (1H, d, J=8.1 Hz),8.27 (1H, d, J=8.1 Hz), 8.47 (1H, s), 12.70-13.00 (1H, br)

PRODUCTION EXAMPLE 8a 7-Amino-3-cyano-1H-indole

2.80 g (15.0 mmol) of the compound of Production Example 7a wassuspended in 100 ml of methanol and hydrogenated under normal pressureat normal temperature in the presence of palladium-carbon. Afterfiltering off the catalyst, the reaction mixture was concentrated todryness, to give 2.31 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 5.32, 5.34 (2H, s+s), 6.47 (1H, d, J=7.5 Hz),6.81 (1H, d, J=7.9 Hz), 6.94 (1H, dd, J=7.9, 7.5 Hz), 8.13 (1H, s),11.55-11.90 (1H, br),

PRODUCTION EXAMPLE 9a 7-Amino-3,4-dichloro-1H-indole

7-Bromo-4-chloro-1H-indole obtained from 2-bromo-5-chloronitrobenzene inthe same manner as in Production Example 1a was first chlorinated in thesame manner as in Production Example 3a, and then the bromo group wasconverted into an amino group, to give the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 5.26 (2H, s), 6.29 (1H, d, J=8.1 Hz), 6.74 (1H,d, J=8.1 Hz), 7.45-7.51 (1H, m), 11.08-11.27 (1H, m)7-Amino-4-tert-butyldimethylsilyloxy-3-chloro-1H-indole was synthesizedin the same manner.

PRODUCTION EXAMPLE 10a 7-Amino-3-chloro-1H-indole

1.076 g (6.64 mmol) of 7-nitro-1H-indole was dissolved in 30 ml ofacetonitrile, and 920 mg (6.89 mmol) of N-chlorosuccinimide was addedthereto. After stirring at room temperature for 36 hours, an aqueoussaturated sodium bicarbonate was added thereto. The precipitates werecollected by filtration and washed with water, to give 1.2 g of3-chloro-7-nitro-1H-indole. 863 mg (4.39 mmol) of the powder wassuspended in 10 ml of ethanol, and 4.95 g (21.9 mmol) of stannouschloride.dihydrate and 100 μl of concentrated hydrochloric acid wereadded thereto. After heating under reflux for 30 minutes, an aqueoussaturated sodium bicarbonate was added thereto and the insoluble matterswere filtered off. After extracting by adding ethyl acetate thereto, theextract was dried over magnesium sulfate and concentrated. The residuewas purified by silica gel column chromatography, to give 490 mg of thetitle compound.

The title compound was also obtained by hydrogenating3-chloro-7-nitro-1H-indole at normal temperature under normal pressurein the presence of a platinum-carbon catalyst.

¹H-NMR (DMSO-d₆) δ(ppm): 5.14 (2H, s), 6.36 (1H, dd, J=7.5, 1.0 Hz),6.68 (1H, dd, J=7.9, 0.73 Hz), 6.81 (1H, dd, J=7.9, 7.5 Hz), 7.39 (1H,d, J=2.7 Hz), 10.85 (1H, br s)

PRODUCTION EXAMPLE 11a 4-(2-Sulfamoylethyl)benzenesulfonyl chloride

1.3 g (7.3 mmol) of 2-phenylethanesulfonamide was added to 2.4 g (36.5mmol) of chlorosulfonic acid under ice-cooling over 20 minutes, followedby stirring at room temperature for further 90 minutes. The reactionmixture solution was poured into ice-water, and then extracted withethyl acetate. The extract was successively washed with an aqueoussaturated sodium bicarbonate and brine, and dried over magnesiumsulfate. The solvent was evaporated, to give 1.6 g of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.97-3.02 (2H, m), 3.21-3.26 (2H, m), 7.21 (2H,d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz)

The following raw material compounds were synthesized in the samemanner.

-   4-[2-(methylsulfonyl)ethyl]benzenesulfonyl chloride-   4-[2-(N-methylmethanesulfonamide)ethyl]benzenesulfonyl chloride-   4-[2-(methanesulfonamido)ethyl]benzenesulfonyl chloride-   4-(N-methylacetamido)benzenesulfonyl chloride

PRODUCTION EXAMPLE 12a 5-Bromo-7-nitro-1H-indole

5.05 g (17.7 mmol) of 1-acetyl-5-bromo-7-nitroindoline was dissolvedinto a mixed solution of 6 ml of ethanol and 40 ml of 6 N hydrochloricacid, followed by heating under reflux for 3 hours. After neutralizingby adding sodium carbonate thereto, the mixture was extracted with ethylacetate. The extract was washed with water, dried over magnesium sulfateand concentrated. Then, the residue was purified by silica gel columnchromatography, to give 4.13 g of 5-bromo-7-nitroindoline. 301 mg (1.24mmol) of this compound was added to 10 ml of toluene, and then 580 mg(2.55 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was addedthereto. After heating under reflux for 3.5 hours while stirring, theinsoluble matters were filtered off and the filtrate was concentrated.The residue was purified by silica gel column chromatography, to give252 mg of the title compound.

PRODUCTION EXAMPLE 13a 5-Bromo-3-formyl-7-nitro-1H-indole

210 mg (1.4 mmol) of phosphorous oxychloride was added to 1.0 g (14mmol) of dimethylformamide at 0° C. in nitrogen atmosphere, followed bystirring for 30 minutes. 240 mg (1.0 mmol) of the compound of ProductionExample 12a was added thereto at 0° C., and the mixture was stirred at0° C. for 20 minutes and then at 100° C. for 30 minutes. The reactionmixture was ice-cooled and then poured into ice-water. The mixture wasstirred for 30 minutes, while it was kept at pH 7 to 8 by adding a 1Naqueous sodium hydroxide. The resulting precipitates were collected byfiltration, washed with water and then purified by silica gel columnchromatography, to give 239 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 8.31 (1H, d, J=1.8 Hz), 8.55 (1H, s), 8.65 (1H,d, J=1.8 Hz), 10.05 (1H, s), 12.89 (1H, br s)

PRODUCTION EXAMPLE 14a 7-Amino-5-bromo-3-cyano-1H-indole

214 mg (0.8 mmol) of 5-bromo-3-cyano-7-nitro-1H-indole obtained from thecompound of Production Example 13a in the same manner as in ProductionExample 7a was dissolved in a mixed solution of 10 ml of methanol and 10ml of tetrahydrofuran. The mixture was hydrogenated at 3.0 kg/cm² in thepresence of platinum oxide, then the catalyst was filtered off and thefiltrate was concentrated to dryness, to give 189 mg of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 5.68-5.71 (2H, m), 6.60 (1H, d, J=2.0 Hz), 6.91(1H, d, J=2.0 Hz), 8.16 (1H, s)

PRODUCTION EXAMPLE 15a 3-Acetyl-7-amino-1H-indole

11 ml (11 mmol) of a hexane solution containing 1.0 M dimethylaluminumchloride was added to a dichloromethane solution (50 ml) containing 1.2g (7.5 mmol) of 7-nitro-1H-indole at 0° C. in nitrogen atmosphere. Then,2.1 ml (29.5 mmol) of acetyl chloride was added thereto at 0° C.,followed by stirring at room temperature for 4 hours. An aqueoussaturated ammonium chloride was added to the reaction system and theresulting precipitates were collected by filtration. These precipitateswere washed sufficiently with hot ethanol. The washing solution wascombined with the filtrate and the combined solution was concentrated.Water was added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with brine, and dried over magnesiumsulfate. The solvent was evaporated, and the residue was purified bysilica gel column chromatography, to give 3-acetyl-7-nitro-1H-indole.The product was dissolved in 100 ml of methanol and hydrogenated atnormal temperature under normal pressure in the presence ofpalladium-carbon. After filtering off the catalyst, the filtrate wasconcentrated to dryness, to give 790 mg of the title compound.

SYNTHETIC EXAMPLE 1a N-(1H-Indole-7-yl)-4-nitrobenzenesulfonamide

1.50 g (11.3 mmol) of the compound of Production Example 2a wasdissolved in 40 ml of pyridine, followed by adding 2.57 g (11.6 mmol) of4-nitrobenzenesulfonyl chloride thereto at room temperature understirring. After stirring at room temperature overnight, the solvent wasevaporated, and to the residue were added ethyl acetate and 0.2 Nhydrochloric acid. The organic layer was separated, washed with water,dried over magnesium sulfate. Then, the solvent was evaporated, and theresidue was purified by silica gel column chromatography, to give 3.50 gof the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.42 (1H, dd, J=2.8, 2.0 Hz), 6.66 (1H, d,J=7.6 Hz), 6.83 (1H, dd, J=8.0, 7.6 Hz), 7.31 (1H, dd, J=3.2, 2.8 Hz),7.36 (1H, d, J=8.0 Hz), 7.94-8.02 (2H, m), 8.30-8.38 (2H, m), 10.23 (1H,s), 10.74-10.87 (1H, m)

SYNTHETIC EXAMPLE 2aN-(3-Chloro-1H-indole-7-yl)-4-nitrobenzenesulfonamide

8.98 g (28.3 mmol) of the compound of Synthetic Example 1a was dissolvedin a mixed solution of 280 ml of dichloromethane and 7 ml ofdimethylformamide, followed by adding 4.16 g (31.2 mmol) ofN-chlorosuccinimide under stirring in a nitrogen atmosphere. Afterstirring at room temperature for 1.5 hours, 50 ml of water was addedthereto and the mixture was concentrated until the amount of the mixturebecame about 80 ml. The organic layer was separated by adding ethylacetate and 0.2 N hydrochloric acid thereto, successively washed withaqueous saturated sodium bicarbonate and brine, and dried over magnesiumsulfate. Then, the solvent was evaporated, and the residue was purifiedby silica gel column chromatography, to give 7.98 g of the titlecompound.

Melting point: 199.5 to 200.5° C. (recrystallized from chloroform)

¹H-NMR (DMSO-d₆) δ(ppm): 6.72 (1H, d, J=7.6 Hz), 6.96 (1H, dd, J=8.0,7.6 Hz), 7.31 (1H, d, J=8.0 Hz), 7.47-7.53 (1H, m), 7.92-8.02 (2H, m),8.30-8.41 (2H, m), 10.33 (1H, s), 11.07-11.22 (1H, m)

SYNTHETIC EXAMPLE 3a4-Amino-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide

7.98 g (22.7 mmol) of the compound of Synthetic Example 2a was dissolvedin 220 ml of methanol, followed by heating under reflux with stirring.10 ml of concentrated hydrochloric acid and 7.40 g of a zinc powder wereadded thereto three times at intervals of 10 minutes, followed byrefluxing for further 10 minutes. After cooling, the reaction mixturewas neutralized by adding significantly excess sodium bicarbonate andthe insoluble matters were filtered off. After concentrating thefiltrate, the residue was dissolved in ethyl acetate. The mixture wassuccessively washed with an aqueous saturated sodium bicarbonate, a 2Naqueous sodium carbonate solution and brine, dried over magnesiumsulfate, and then the solvent was evaporated. The residue was purifiedby silica gel column chromatography, to give 7.21 g of the titlecompound.

Melting point: 174.5 to 176° C. (recrystallized from ethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 5.97 (2H, br s), 6.48 (2H, d, J=8.8 Hz), 6.88(1H, d, J=7.6 Hz), 6.95 (1H, dd, J=8.0, 7.6 Hz), 7.19 (1H, d, J=8.0 Hz),7.36 (2H, d, J=8.8 Hz), 7.46 (1H, d, J=2.4 Hz), 9.56 (1H, s),10.86-10.98 (1H, m)

SYNTHETIC EXAMPLE 4aN-(3-Chloro-1H-indole-7-yl)-4-(methanesulfonamide)benzenesulfonamide

68 mg (0.211 mmol) of the compound of Synthetic Example 3a was dissolvedin 1 ml of pyridine, followed by adding 15 μl (0.194 mmol) ofmethanesulfonyl chloride. After stirring at room temperature overnight,an aqueous sodium bicarbonate was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was successively washedwith dilute hydrochloric acid and water, dried over magnesium sulfate,and concentrated. Then, the residue was purified by silica gel thinlayer chromatography, to give 76 mg of the title compound.

Melting point: 213.5 to 214° C. (decomposed) (recrystallized fromethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 3.08 (3H, s), 6.83 (1H, d, J=7.5 Hz), 6.96 (1H,dd, J=7.9, 7.7 Hz), 7.23 (2H, d, J=8.8 Hz), 7.24 (1H, d, J=7.5 Hz), 7.47(1H, d, J=2.7 Hz), 7.68 (2H, d, J=8.8 Hz), 9.92 (1H, br s), 10.38 (1H,br s), 10.99 (1H, br s)

SYNTHETIC EXAMPLE 5a 4-Bromomethyl-N-(1H-indole-7-yl)benzenesulfonamide

4-Bromomethylbenzenesulfonyl chloride and the compound of ProductionExample 2a were reacted in tetrahydrofuran at room temperature in thepresence of an equivalent mol of pyridine and treated in the same manneras in Synthetic Example 1am, to give the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 4.70 (2H, s), 6.40 (1H, dd, J=3.1, 1.1 Hz),6.71 (1H, ddd, J=7.4, 3.2, 0.92 Hz), 6.81 (1H, ddd, J=8.1, 7.4, 0.92Hz), 7.29-7.32 (2H, m), 7.57 (2H, d, J=8.2 Hz), 7.73 (2H, d, J=8.4 Hz),9.96 (1H, br s), 10.75 (1H, br s)

SYNTHETIC EXAMPLE 6aN-(1,3-Dihydro-2H-indole-2-one-7-yl)-4-methylbenzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

Melting point: started decomposing gradually from a temperature close to246° C. and decomposed rapidly at 267 to 269° C. (recrystallized fromdioxane).

SYNTHETIC EXAMPLE 7a3-Chloro-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide

2.18 g (7.11 mmol) of 3-chloro-N-(1H-indole-7-yl)benzenesulfonamidesynthesized in the same manner as in Synthetic Example 1a waschlorinated in the same manner as in Example 2a, to give 1.86 g of thetitle compound.

Melting point: 180 to 181° C. (recrystallized fromdichloromethane/diisopropyl ether)

¹H-NMR (DMSO-d₆) δ(ppm): 6.73 (1H, d, J=7.6 Hz), 6.97 (1H, dd, J=8.0,7.6 Hz), 7.30 (1H, d, J=8.0 Hz), 7.45-7.51 (1H, m), 7.51-7.76 (4H, m),10.09 (1H, s), 11.02-11.18 (1H, m)

SYNTHETIC EXAMPLE 8a4-Amino-N-(3,4-dichloro-1H-indole-7-yl)benzenesulfonamide

2.03 g of the title compound was obtained from 2.43 g (6.29 mmol) ofN-(3,4-dichloro-1H-indole-7-yl)-4-nitrobenzenesulfonamide synthesized inthe same manner as in Synthetic Example 1a in the same manner as inExample 3a.

Melting point: 205 to 206.5° C. (decomposed) (recrystallized fromethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.00 (2H, s), 6.50 (2H, d, J=8.4 Hz), 6.77 (1H,d, J=8.0 Hz), 6.94 (1H, d, J=8.0 Hz), 7.35 (2H, d, J=8.4 Hz), 7.51-7.58(1H, m), 9.57 (1H, s), 11.20-11.38 (1H, m)

SYNTHETIC EXAMPLE 9a 4-[N-(1H-Indole-7-yl)sulfamoyl]benzoic acid

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.40 (1H, dd, J=2.9, 1.9 Hz), 6.67 (1H, d,J=7.5 Hz), 6.82 (1H, dd, J=7.9, 7.5 Hz), 7.31 (1H, dd, J=2.9, 2.7 Hz),7.33 (1H, d, J=7.9 Hz), 7.81-7.88 (2H, m), 7.99-8.07 (2H, m), 10.07 (1H,s), 10.73-10.83 (1H, m), 13.30-13.58 (1H, br)

SYNTHETIC EXAMPLE 10aN-(3-Chloro-1H-indole-7-yl)-4-cyanobenzenesulfonamide

76 mg of the title compound was obtained in the same manner as inExample 2a, from 100 mg of 4-cyano-N-(1H-indole-7-yl)benzenesulfonamidesynthesized in the same manner as in Synthetic Example 1a.

Melting point: 210 to 211° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.71 (1H, dd, J=7.6, 0.8 Hz), 6.96 (1H, dd,J=8.0, 7.6 Hz), 7.30 (1H, d, J=8.0 Hz), 7.48 (1H, dd, J=2.4, 0.8 Hz),7.82-7.90 (2H, m), 7.97-8.05 (2H, m), 10.25 (1H, s), 11.04-11.15 (1H, m)

SYNTHETIC EXAMPLE 11a3-Chloro-N-(3-chloro-4-hydroxy-1H-indole-7-yl)benzenesulfonamide

52 mg of the title compound was obtained in the same manner as inExample 2a, from 100 mg of3-chloro-N-(4-methoxy-1H-indole-7-yl)benzenesulfonamide synthesized inthe same manner as in Synthetic Example 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 3.79 (3H, s), 6.37 (1H, d, J=8.4 Hz), 6.45 (1H,d, J=8.4 Hz), 7.24-7.31 (1H, m), 7.48-7.77 (4H, m), 9.76 (1H, s),11.06-11.17 (1H, m)

SYNTHETIC EXAMPLE 12a3-Chloro-N-(3-chloro-4-hydroxy-1H-indole-7-yl)benzenesulfonamide

220 mg (0.47 mmol) ofN-(4-tert-butyldimethylsilyloxy-3-chloro-1H-indole-7-yl)-3-chlorobenzenesulfonamidesynthesized in the same manner as in Synthetic Example 1a was added to amixed solution (2 ml) of an aqueous 40% hydrogen fluoridesolution/acetonitrile (1:10). After stirred at room temperatureovernight, water was added thereto and the mixture was extracted withethyl acetate. The extract was dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gel columnchromatography, to give 141 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.15 (1H, dd, J=8.2, 1.5 Hz), 6.26 (1H, d,J=8.2 Hz), 7.12 (1H, s), 7.47-7.64 (4H, m), 9.54 (1H, s), 10.85 (1H, s)

SYNTHETIC EXAMPLE 13a N-(1H-Indazole-7-yl)-4-methoxybenzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

Melting point: 155 to 156° C. (recrystallized from ethylacetate-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 3.77 (3H, s), 6.91-6.99 (2H, m), 6.98-7.07 (2H,m), 7.45-7.53 (1H, m), 7.64-7.74 (2H, m), 8.01-8.07 (1H, m), 9.97 (1H,s), 12.61-12.72 (1H, m)

SYNTHETIC EXAMPLE 14a6-Chloro-N-(3-chloro-1H-indole-7-yl)-3-pyridinesulfonamide

The title compound was obtained by chlorinating6-chloro-N-(1H-indole-7-yl)-3-pyridinesulfonamide obtained by reacting6-chloro-3-pyridinesulfonyl chloride and the compound of ProductionExample 2a in the same manner as in Example 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.73 (1H, d, J=7.7 Hz), 6.97 (1H, dd, J=7.9,7.7 Hz), 7.30 (1H, d, J=7.9 Hz), 7.46 (1H, d, J=2.6 Hz), 7.67 (1H, d,J=8.4 Hz), 8.03 (1H, dd, J=8.4, 2.6 Hz), 8.62 (1H, d, J=2.6 Hz),10.18-10.34 (1H, br), 11.06-11.17 (1H, m)

SYNTHETIC EXAMPLE 15aN-(3-Chloro-1H-indole-7-yl)-4-(methylthiomethyl)benzenesulfonamide

1.97 g (5.37 mmol) of the compound of Synthetic Example 5a was dissolvedin 10 ml of tetrahydrofuran. To the mixture were added 10 ml (39.4 mmol)of an aqueous 15% sodium methylthiolate solution and a catalytic amountof methyltrioctylammonium chloride at room temperature, followed bystirring over night. 20 ml of water was added thereto, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater, dried over magnesium sulfate and concentrated. Then, the residuewas purified by silica gel column chromatography, to give 1.51 g ofN-(1H-indole-7-yl)-4-(methylthiomethyl)benzenesulfonamide. The productwas chlorinated in the same manner as in Example 2a, to give 839 mg ofthe title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.87 (3H, s), 3.70 (2H, s), 6.77 (1H, dd,J=7.6, 2.1 Hz), 6.94 (1H, dd, J=7.9, 7.7 Hz), 7.24 (1H, d, J=7.9 Hz),7.42 (2H, d, J=8.2 Hz), 7.47 (1H, d, J=2.6 Hz), 7.67 (2H, d, J=8.4 Hz),9.96 (1H, br s), 11.01 (1H, br s)

SYNTHETIC EXAMPLE 16a3-Chloro-N-(3-formyl-1H-indole-7-yl)benzenesulfonamide

1.3 ml (13.9 mmol) of phosphorous oxychloride was added dropwise to 14.5ml of dimethylformamide at 10° C. or less under stirring in nitrogenatmosphere. After stirring at about 5° C. for 30 minutes, 2.50 g (8.15mmol) of 3-chloro-N-(1H-indole-7-yl)benzenesulfonamide synthesized inthe same manner as in Example 1 was added thereto in three portions.After stirring at about 5° C. for further 30 minutes, 200 ml of cooledwater was added thereto. The reaction mixture was adjusted to pH about14 by adding a 1N aqueous sodium hydroxide and then to pH about 2 byadding 1N hydrochloric acid, and then extracted by adding ethyl acetatethereto. The organic layer was washed with brine, dried over magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography, to give 1.45 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.70 (1H, dd, J=7.6, 0.8 Hz), 7.06 (1H, dd,J=8.0, 7.6 Hz), 7.51-7.75 (4H, m), 7.93 (1H, d, J=8.0 Hz), 8.22-8.28(1H, m), 9.93 (1H, s), 10.17 (1H, s), 11.86-11.98 (1H, m)

SYNTHETIC EXAMPLE 17a3-Chloro-N-(3-cyano-1H-indole-7-yl)benzenesulfonamide

274 mg (3.94 mmol) of hydroxylamine hydrochloride and 0.32 ml (3.96mmol) of pyridine were added to a dimethylformamide solution (18 ml)containing 1.20 g (3.58 mmol) of the compound of Synthetic Example 16aat 70 to 80° C. under stirring. After stirring for 2.5 hours as it was,437 mg (3.94 mmol) of selenium dioxide and about 100 mg of magnesiumsulfate powder were added thereto. After stirring at the sametemperature for further 2 hours, the solvent was evaporated. To theresidue was added ethyl acetate, and the insoluble matters werecollected by filtration. The filtrate was successively washed with 0.1 Nhydrochloric acid and brine, dried over magnesium sulfate and thesolvent was evaporated. The residue was purified by silica gel columnchromatography, to give 678 mg of the title compound.

Melting point: 204.5 to 205° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.71 (1H, d, J=7.6 Hz), 7.08 (1H, dd, J=8.0,7.6 Hz), 7.47 (1H, d, J=8.0 Hz), 7.50-7.76 (4H, m), 8.17-8.25 (1H, m),10.21 (1H, s), 11.92-12.09 (1H, m)

SYNTHETIC EXAMPLE 18a6-Chloro-N-(3-cyano-1H-indole-7-yl)-3-pyridinesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.77 (1H, d, J=7.9 Hz), 7.12 (1H, t, J=7.9 Hz),7.50 (1H, d, J=7.9 Hz), 7.72 (1H, d, J=8.4 Hz), 8.06 (1H, dd, J=8.4, 2.6Hz), 8.23 (1H, d, J=2.6 Hz), 8.65 (1H, d, J=2.6 Hz), 10.34-10.48 (1H,br), 11.98-12.12 (1H, m)

SYNTHETIC EXAMPLE 19aN-(3-Chloro-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide

767 mg (3.0 mmol) of the compound of Production Example 5a and 264 mg(2.0 mmol) of the compound of production Example 2a were reacted andtreated in the same manner as in Example 1a, to give 445 mg ofN-(1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide. The product waschlorinated in the same manner as in Example 2a, to give 349 mg of thetitle compound.

Melting point: started coloring partially in a black color from atemperature close to 220° C. and decomposed gradually from a temperatureclose to 240° C. (recrystallized from ethanol/n-hexane).

¹H-NMR (DMSO-d₆) δ(ppm): 6.75 (1H, d, J=7.6 Hz), 6.96 (1H, dd, J=8.0,7.6 Hz), 7.29 (1H, d, J=7.6 Hz), 7.50 (1H, d, J=2.8 Hz), 7.58 (2H, s),7.90-7.98 (4H, m), 10.23 (1H, s), 11.07-11.17 (1H, m)

SYNTHETIC EXAMPLE 20a3-Chloro-N-(8-imidazo[1,2-a]pyridinyl)benzenesulfonamide hydrochloride

1.97 g (18 mmol) of 2,3-diaminopyridine was dissolved in a mixedsolution of tetrahydrofuran and water, and a tetrahydrofuran solutioncontaining 1.90 g (9.0 mmol) of 3-chlorobenzenesulfonyl chloride wasadded thereto. After stirring at room temperature overnight, the mixturewas concentrated, and water and dichloromethane were added to theresidue. The organic layer was separated, and the wall of the reactorwas rubbed. The resulting crystals were collected by filtration, to give1.41 g of N-(2-amino-3-pyridiny)-3-chlorobenzenesulfonamide. 530 mg(1.87 mmol) of the crystals was dissolved in methanol and 367 mg (1.87mmol) of an aqueous 40% chloroacetoaldehyde solution was added thereto.After heating under reflux for 4 hours, the mixture was concentrated todryness. A small amount of methanol was added to the residue and thecrystals were collected by filtration, to give 373 mg of the titlecompound.

Melting point: gradually decomposed from a temperature close to 210° C.(recrystallized from ethanol)

SYNTHETIC EXAMPLE 21aN-(3,4-Dichloro-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide

429 mg (1.68 mmol) of the compound of Production Example 5a and 250 mg(1.24 mmol) of the compound of Production Example 9a were reacted andtreated in the same manner as in Example 1a, to give 200 mg of the titlecompound.

Melting point: started coloring from a temperature close to 282° C. andgradually decomposed (recrystallized from ethanol/ethyl ether).

¹H-NMR (DMSO-d₆) δ(ppm): 6.62 (1H, d, J=8.1 Hz), 6.95 (1H, d, J=8.1 Hz),7.53-7.62 (3H, m), 7.87-7.99 (4H, m), 10.17-10.33 (1H, br), 11.44-11.56(1H, m)

SYNTHETIC EXAMPLE 22aN-(3-Chloro-1H-indole-7-yl)-4-(methylthio)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.48 (3H, s), 6.82 (1H, dd, J=7.9, 1.5 Hz),6.96 (1H, dd, J=8.1, 7.5 Hz), 7.25 (1H, dd, J=7.9, 0.92 Hz), 7.33 (2H,d, J=8.8 Hz), 7.49 (1H, d, J=2.7 Hz), 7.62 (2H, d, J=8.6 Hz), 9.96 (1H,br s), 11.02 (1H, br s)

SYNTHETIC EXAMPLE 23aN-(3-Chloro-1H-indole-7-yl)-4-(methylsulfonyl)benzenesulfonamide

54.2 mg (0.154 mmol) of the compound of Synthetic Example 22a wasdissolved in a mixed solution of 2 ml of methanol and 1.2 ml of water,to which were then added 30 mg of ammonium molybdate.tetrahydrate and0.6 ml of aqueous 30% hydrogen peroxide at room temperature. Afterstirring overnight, water was added thereto and the mixture wasextracted with ethyl acetate. The extract was washed with water, driedover magnesium sulfate and concentrated. Then, the residue was purifiedby silica gel column chromatography, to give 29.4 mg of the titlecompound.

Melting point: started coloring from a temperature close to 250° C. anddecomposed at 264 to 266° C. (recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 3.28 (3H, s), 6.75 (1H, d, J=7.7 Hz), 6.97 (1H,dd, J=7.9, 7.7 Hz), 7.30 (1H, d, J=8.1 Hz), 7.50 (1H, d, J=2.7 Hz), 7.97(2H, d, J=8.2 Hz), 8.09 (2H, d, J=8.4 Hz), 10.29 (1H, br s), 11.12 (1H,br s)

SYNTHETIC EXAMPLE 24aN-(3-Chloro-1H-indole-7-yl)-4-(methylsulfinyl)benzenesulfonamide

19.9 mg (0.056 mmol) of the compound of Synthetic Example 22a wasdissolved in 2 ml of dichloromethane, followed by adding 10 mg (0.058mmol) of m-chloroperbenzoate under stirring under ice-cooling. After onehour, an aqueous saturated sodium bicarbonate was added thereto, and themixture was extracted with ethyl acetate. The extract was washed withwater, dried over magnesium sulfate and concentrated. Then, the residuewas purified by silica gel thin layer chromatography, to give 14.4 mg ofthe title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.76 (3H, s), 6.78 (1H, dd, J=7.5, 1.1 Hz),6.96 (1H, dt, Jd=0.55 Hz, Jt=7.8 Hz), 7.28 (1H, dd, J=7.6, 0.82 Hz),7.48 (1H, d, J=2.7 Hz), 7.82 (2H, d, J=8.6 Hz), 7.89 (2H, d, J=8.8 Hz),10.15 (1H, br s), 11.06 (1H, br s)

SYNTHETIC EXAMPLE 25a3-Chloro-N-(3-chloro-1H-pyrrolo[3,2-c]pyridine-7-yl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 7.41-7.65 (2H, m), 7.65-7.77 (2H, m), 7.74-7.86(2H, m), 8.40-8.62 (1H, br m), 12.38-12.58 (1H, br), 13.56-13.74 (1H,br)

SYNTHETIC EXAMPLE 26a4-Acetamide-N-(3-chloro-4-methyl-1H-indole-7-yl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

Melting point: decomposed gradually from a temperature close to 225° C.(recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.03 (3H, s), 2.56 (3H, s), 6.54-6.60 (2H, m),7.33 (1H, d, J=2.6 Hz), 7.60 (2H, d, J=9.0 Hz), 7.64 (2H, d, J=9.0 Hz),9.63 (1H, br s), 10.24 (1H, br s), 10.92 (1H, br s)

SYNTHETIC EXAMPLE 27a4-Amino-N-(3-chloro-4-methyl-1H-indole-7-yl)benzenesulfonamide

3.75 g (9.9 mmol) of the compound of Synthetic Example 26a was dissolvedin 25 ml of an aqueous 2 N sodium hydroxide, followed by stirring at100° C. for 2 hours. After returning to room temperature, the mixturewas adjusted to pH 6 by adding acetic acid. The resulting precipitateswere collected by filtration and purified by silica gel columnchromatography, to give 1.1 g of the title compound.

Melting point: decomposed gradually from a temperature close to 230° C.(recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.56 (3H, s), 5.93 (2H, br s), 6.46 (2H, d,J=8.8 Hz), 6.59 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=7.8 Hz), 7.31 (2H, d,J=8.8 Hz), 7.36 (1H, d, J=2.9 Hz), 9.34 (1H, br s), 10.88 (1H, br s)

SYNTHETIC EXAMPLE 28a4-Cyano-N-(3-cyano-1H-indole-7-yl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

Melting point: 250.5 to 252° C. (recrystallized from ethylacetate/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.67 (1H, d, J=7.7 Hz), 7.05 (1H, t, J=7.9 Hz),7.44 (1H, d, J=7.7 Hz), 7.78-7.87 (2H, m), 7.97-8.05 (2H, m), 8.16-8.23(1H, m), 10.28-10.43 (1H, br), 11.92-12.09 (1H, m)

SYNTHETIC EXAMPLE 29a4-Carbamoyl-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide

To a solution of 1.0 g (3.01 mmol) of the compound of Synthetic Example10a added to 4.8 ml of ethanol 2.4 ml were added a 30% aqueous hydrogenperoxide and 360 μl of an aqueous 6 N sodium hydroxide were respectivelyadded in three portions under stirring. (reaction temperature: about 50°C.). After stirring at 50° C. for further 30 minutes, the reactionmixture was acidified by adding dilute hydrochloric acid and thenextracted with ethyl acetate. The organic layer was collected byfractionation, washed with water, dried over magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography, to give 600 mg of the title compound.

Melting point: started coloring and decomposing from a temperature closeto 248° C. and rapidly decomposed at 252.5 to 253.5° C. (recrystallizedfrom ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.76 (1H, d, J=7.5 Hz), 6.95 (1H, dd, J=8.1,7.5 Hz), 7.27 (1H, d, J=8.1 Hz), 7.49 (1H, d, J=2.6 Hz), 7.59 (1H, brs), 7.76-7.83 (2H, m), 7.91-7.98 (2H, m), 8.12 (1H, br s), 10.10 (1H,s), 11.01-11.12 (1H, m)

SYNTHETIC EXAMPLE 30aN-(4-Bromo-1H-indole-7-yl)-4-nitrobenzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.35-6.41 (1H, m), 6.56 (1H, d, J=8.4 Hz), 7.06(1H, dd, J=8.4, 0.8 Hz), 7.41-7.48 (1H, m), 7.92-8.02 (2H, m), 8.30-8.41(2H, m), 10.34 (1H, s), 11.18-11.32 (1H, m)

SYNTHETIC EXAMPLE 31aN-(3-Chloro-4-cyano-1H-indole-7-yl)-4-nitrobenzenesulfonamide

200 mg (0.505 mmol) of the compound of Synthetic Example 30a wasdissolved in 0.8 ml of N-methylpyrrolidone, followed by adding 83 mg(0.91 mmol) of cuprous cyanide. After stirring at 180 to 190° C. for 3hours, 40 ml of ice-water was added thereto. The insoluble matters werecollected by filtration, washed with water, and extracted with hotethanol and hot chloroform. The extract was concentrated and the residuewas purified by silica gel thin layer chromatography, to give 65 mg ofN-(4-cyano-1H-indole-7-yl)-4-nitrobenzenesulfonamide. This product waschlorinated in the same manner as in Example 2, to give 42 mg of thetitle compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.98 (1H, d, J=8.0 Hz), 7.51 (1H, d, J=8.0 Hz),7.79 (1H, d, J=2.8 Hz), 7.99-8.08 (2H, m), 8.31-8.40 (2H, m),10.75-10.95 (1H, br), 11.62-11.73 (1H, m)

SYNTHETIC EXAMPLE 32a4-Amino-N-(3-chloro-4-cyano-1H-indole-7-yl)-benzenesulfonamide

The title compound was obtained from the compound of Synthetic Example31a in the same manner as in synthetic Example 3a.

Melting point: started decomposing from a temperature close to 232° C.and rapidly decomposed at 249.5 to 255° C. (recrystallized fromethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.09 (2H, s), 6.52 (2H, d, J=8.8 Hz), 7.10 (1H,d, J=8.4 Hz), 7.46 (2H, d, J=8.8 Hz), 7.50 (1H, d, J=8.4 Hz), 7.72-7.79(1H, m), 10.20 (1H, s), 11.40-11.59 (1H, m)

SYNTHETIC EXAMPLE 33a6-Amino-N-(3-chloro-1H-indole-7-yl)-3-pyridinesulfonamide

2.48 g (7.25 mmol) of the compound of Synthetic Example 14a and 679 mg(5.07 mmol) of lithium iodide were added to 25 ml of ethanol. 10 ml ofliquid ammonia was added thereto, and the mixture was heated at 120° C.for 26 hours in a sealed tube and then concentrated. The residue wasdissolved in ethyl acetate, and the mixture was successively washed withan aqueous saturated sodium bicarbonate and water, dried over magnesiumsulfate and concentrated. Then, the residue was purified by silica gelcolumn chromatography, to give 982 mg of the title compound.

Melting point: 206 to 207° C. (recrystallized from ethyl-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.37 (1H, d, J=8.8 Hz), 6.83-6.94 (1H, m), 6.88(2H, br s), 6.99 (1H, dd, J=7.9, 7.7 Hz), 7.25 (1H, dd, J=7.9, 0.7 Hz),7.48 (1H, d, J=2.7 Hz), 7.56 (1H, dd, J=8.8, 2.4 Hz), 8.14 (1H, d, J=2.4Hz), 9.70 (1H, s), 10.92-11.03 (1H, m)

SYNTHETIC EXAMPLE 34aN-(3-Chloro-1H-indole-7-yl)-4-(methylsulfinylmethyl)benzenesulfonamide

The title compound was obtained by oxidizing the compound of SyntheticExample 15a in the same manner as in Example 24a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.41 (3H, s), 3.98 (1H, d, J=12.6 Hz), 4.18(1H, d, J=12.8 Hz), 6.77 (1H, d, J=7.5 Hz), 6.94 (1H, dd, J=7.9, 7.7Hz), 7.25 (1H, d, J=7.9 Hz), 7.43 (2H, d, J=8.1 Hz), 7.47 (1H, d, J=2.8Hz), 7.73 (2H, d, J=8.1 Hz), 10.01 (1H, br s), 11.03 (1H, br s)

SYNTHETIC EXAMPLE 35aN-(3-Chloro-1H-indole-7-yl)-4-(2-sulfamoylethyl)benzenesulfonamide

865 mg (3.05 mmol) of the compound of Production Example 11a was reactedwith 376 mg (2.84 mmol) of the compound of Production Example 2a andtreated in the same manner as in Example 1a. The resulting 957 mg ofN-(1H-indole-7-yl)-4-(2-sulfamoylethyl)benzenesulfonamide waschlorinated in the same manner as in Example 2a, to give 980 mg of thetitle compound.

Melting point: 217 to 219° C. (decomposed) (recrystallized fromethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 3.01-3.06 (2H, m), 3.23-3.28 (2H, m), 6.81 (1H,dd, J=7.5, 0.37 Hz), 6.88 (2H, br s), 6.95 (1H, dd, J=8.1, 7.5 Hz), 7.24(1H, dd, J=7.8, 0.37 Hz), 7.42 (2H, d, J=8.4 Hz), 7.49 (1H, d, J=2.6Hz), 7.68 (2H, d, J=8.2 Hz), 9.99 (1H, br s), 11.02 (1H, br s)

SYNTHETIC EXAMPLE 36aN-(3-Chloro-1H-indole-7-yl)-4-[2-(methylsulfonyl)ethyl]benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

Melting point: started coloring from a temperature close to 180° C. anddecomposed at 201 to 203° C. (recrystallized from ethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.92 (3H, s), 3.01-3.07 (2H, m), 3.40-3.46 (2H,m), 6.81 (1H, d, J=7.9 Hz), 6.94 (1H, dd, J=7.9, 7.7 Hz), 7.24 (1H, d,J=7.7 Hz), 7.45 (2H, d, J=8.2 Hz), 7.49 (1H, d, J=2.7 Hz), 7.68 (2H, d,J=8.2 Hz), 9.99 (1H, br s), 11.03 (1H, br s)

SYNTHETIC 37a 6-Amino-N-(3-cyano-1H-indole-7-yl)-3-pyridinesulfonamide

The compound of Synthetic Example 18a was aminated in the same manner asin Example 33a, to give the title compound.

Melting point: 300° C. or more (recrystallized from ethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.39 (1H, d, J=9.0 Hz), 6.88 (1H, d, J=7.7 Hz),6.89 (2H, s), 7.11 (1H, dd, J=7.9, 7.7 Hz), 7.41 (1H, dd, J=7.9, 0.7Hz), 7.55 (1H, dd, J=9.0, 2.6 Hz), 8.12 (1H, d, J=2.6 Hz), 8.19 (1H, s),9.72-9.90 (1H, br), 11.78-11.92 (1H, m)

SYNTHETIC EXAMPLE 38a4-Acetamido-3-chloro-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.14 (3H, s), 6.77 (1H, d, J=7.7 Hz), 6.98 (1H,dd, J=7.9, 7.7 Hz), 7.29 (1H, d, J=7.9 Hz), 7.50 (1H, d, J=2.7 Hz), 7.64(1H, dd, J=8.6, 2.2 Hz), 7.75 (1H, d, J=2.2 Hz), 8.04 (1H, d, J=8.6 Hz),9.69 (1H, br s), 10.04 (1H, br s), 11.11 (1H, br s)

SYNTHETIC EXAMPLE 39a N-(3-cyano-1H-indole-7-yl)-8-quinolinesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.68 (1H, d, J=7.3 Hz), 6.89 (1H, dd, J=7.9,7.7 Hz), 7.25 (1H, d, J=8.1 Hz), 7.69-7.74 (2H, m), 8.21 (1H, d, J=2.9Hz), 8.30 (1H, dd, J=8.2, 1.3 Hz), 8.35 (1H, dd, J=7.4, 1.4 Hz), 8.54(1H, dd, J=8.3, 1.7 Hz), 9.15 (1H, dd, J=4.3, 1.7 Hz), 10.04 (1H, br s),12.14 (1H, br s)

SYNTHETIC EXAMPLE 40a5-Chloro-N-(3-cyano-1H-indole-7-yl)-2-thiophenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.88 (1H, ddd, J=7.7, 2.2, 0.73 Hz), 7.16 (1H,dd, J=7.9, 7.7 Hz), 7.20 (1H, d, J=4.0 Hz), 7.36 (1H, d, J=4.2 Hz), 7.51(1H, d, J=8.1 Hz), 8.23 (1H, d, J=3.1 Hz), 10.42 (1H, br s), 12.01 (1H,br s)

SYNTHETIC EXAMPLE 41aN-(3-Chloro-1H-indole-7-yl)-4-(methoxycarbonylamino)benzenesulfonamide

170 mg (1.8 mmol) of methyl chloroformate was added to a pyridinesolution (1 ml) containing 38 mg (0.18 mmol) of the compound ofSynthetic Example 3a, followed by stirring at room temperatureovernight. The reaction mixture was concentrated and the residue waspurified by silica gel column chromatography, to give 20 mg of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 3.65 (3H, s), 6.80 (1H, d, J=7.7 Hz), 6.93 (1H,t, J=7.9 Hz), 7.21 (1H, dd, J=7.7, 0.37 Hz), 7.45 (1H, d, J=2.7 Hz),7.51 (2H, d, J=9.0 Hz), 7.63 (2H, d, J=8.8 Hz), 9.85 (1H, br s), 10.07(1H, s), 10.97 (1H, br s)

SYNTHETIC EXAMPLE 42a4-Acetyl-N-(3-cyano-1H-indole-7-yl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.60 (3H, s), 6.74 (1H, d, J=7.7 Hz), 7.05 (1H,dd, J=7.9, 7.7 Hz), 7.42 (1H, d, J=7.9 Hz), 7.81-7.88 (2H, m), 8.03-8.10(2H, m), 8.21 (1H, s), 10.18-10.50 (1H, br), 11.92-12.07 (1H, m)

SYNTHETIC EXAMPLE 43aN-(3-Chloro-1H-indole-7-yl)-4-(N-methoxysulfamoyl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 3.65 (3H, s), 6.73 (1H, d, J=7.6 Hz), 6.96 (1H,dd, J=8.0, 7.6 Hz), 7.30 (1H, d, J=8.0 Hz), 7.50 (1H, d, J=2.4 Hz), 7.98(4H, s), 10.29 (1H, br s), 10.76 (1H, br s), 11.12 (1H, br s)

SYNTHETIC EXAMPLE 44a N-(3-Cyano-1H-indole-7-yl)-β-styrenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 7.14-7.20 (2H, m), 7.32 (2H, s), 7.35-7.47 (4H,m), 7.60-7.68 (2H, m), 8.23 (1H, s), 9.70-10.03 (1H, br), 11.85-12.12(1H, br)

SYNTHETIC EXAMPLE 45a3-Chloro-N-(3-cyano-1H-indole-7-yl)-2-methylbenzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.61 (3H, s), 6.69 (1H, d, J=7.7 Hz), 7.04 (1H,t, J=7.9 Hz), 7.36 (1H, dd, J=8.1, 7.9 Hz), 7.42 (1H, d, J=7.9 Hz), 7.73(1H, dd, J=8.1, 1.1 Hz), 7.77 (1H, dd, J=8.0, 0.82 Hz), 8.25 (1H, d,J=3.1 Hz), 10.37 (1H, s), 11.99 (1H, br s)

SYNTHETIC EXAMPLE 46aN-(3-Chloro-1H-indole-7-yl)-6-isopropylamino-3-pyridinesulfonamide

400 mg (1.17 mmol) of the compound of Synthetic Example 14a and 0.80 ml(9.39 mmol) of isopropylamine were added to 5 ml of dioxane, followed byheating at 100° C. for 7.5 hours in a sealed tube. After concentrating,the mixture was dissolved in ethyl acetate, which was then successivelywashed with aqueous dilute citric acid, an aqueous saturated sodiumbicarbonate and water. The mixture was dried over magnesium sulfate, andthen concentrated. The residue was purified by silica gel thin layerchromatography, to give 235 mg of the title compound.

Melting point: started coloring from the temperature close to 210° C.and decomposed at 213 to 215° C. (recrystallized from ethylacetate/n-hexane).

¹H-NMR (DMSO-d₆) δ(ppm): 1.09 (6H, d, J=6.6 Hz), 3.90-4.08 (1H, m), 6.39(1H, d, J=9.0 Hz), 6.90-7.05 (2H, m), 7.24 (1H, d, J=7.9 Hz), 7.33 (1H,d, J=7.7 Hz), 7.48 (1H, d, J=2.4 Hz), 7.54 (1H, dd, J=9.0, 2.6 Hz), 8.22(1H, d, J=2.6 Hz), 9.65-9.84 (1H, br), 10.88-11.04 (1H, m)

SYNTHETIC EXAMPLE 47aN-(3-Chloro-1H-indole-7-yl)-6-[[2-(dimethylamino)ethyl]amino]-3-pyridinesulfonamide

The title compound was obtained from the compound of Synthetic Example14a and N,N-dimethylethylenediamine in the same manner as in SyntheticExample 46a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.14 (6H, s), 2.35 (2H, t, J=6.6 Hz), 3.24-3.44(2H, m), 6.48 (1H, d, J=9.0 Hz), 6.92 (1H, d, J=7.7 Hz), 6.99 (1H, dd,J=7.9, 7.7 Hz), 7.22 (1H, d, J=7.9 Hz), 7.27-7.39 (1H, m), 7.47 (1H, d,J=2.4 Hz), 7.54 (1H, dd, J=9.0, 2.6 Hz), 8.21 (1H, d, J=2.6 Hz),10.91-11.03 (1H, m)

SYNTHETIC EXAMPLE 48a N-(3-Cyano-1H-indole-7-yl)-2-furansulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.62 (1H, ddd, J=3.7, 1.8, 0.37 Hz), 6.78 (1H,d, J=7.5 Hz), 7.04 (1H, d, J=3.5 Hz), 7.12 (1H, t, J=7.9 Hz), 7.49 (1H,d, J=8.1 Hz), 7.99-8.00 (1H, m), 8.23 (1H, d, J=3.1 Hz), 10.49 (1H, brs), 12.04 (1H, br s)

SYNTHETIC EXAMPLE 49aN-(3-Chloro-1H-indole-7-yl)-4-[(dimethylaminosulfonyl)amino]benzenesulfonamide

The title compound was obtained from the compound of Synthetic Example3a and dimethylsulfamoyl chloride in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.66 (6H, s), 6.81 (1H, dd, J=7.7, 0.92 Hz),6.95 (1H, dd, J=7.9, 7.7 Hz), 7.20 (2H, d, J=8.8 Hz), 7.23 (1H, d, J=8.1Hz), 7.47 (1H, d, J=2.7 Hz), 7.64 (2H, d, J=8.8 Hz), 10.98 (1H, br s)

SYNTHETIC EXAMPLE 50aN-(3-Methyl-1H-indole-7-yl)-4-(methylsulfonyl)benzenesulfonamide

580 mg (15.3 mmol) of sodium borohydride and 150 mg of 10%palladium-carbon were added to a 2-propanol suspension (25 ml)containing 300 mg (1.58 mmol) of 3-formyl-7-nitro-1H-indole, followed byrefluxing for 6 hours. After water was added to the reaction system, thecatalyst was filtered off. The filtrate was extracted with ethylacetate, and the extract was washed with brine and then dried overmagnesium sulfate. The solvent was evaporated, and the residue wasdissolved in 5 ml of pyridine. The mixture was reacted and treated with170 mg (0.67 mmol) of 4-(methylsulfonyl)benzenesulfonyl chloride in thesame manner as in Example 1a, to give 149 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.18 (3H, s), 3.24 (3H, s), 6.69 (1H, d, J=7.7Hz), 6.81 (1H, t, J=7.7 Hz), 7.06 (1H, br s), 7.25 (1H, d, J=7.8 Hz),7.95 (2H, d, J=8.8 Hz), 8.04 (2H, d, J=8.2 Hz), 10.14 (1H, br s), 10.40(1H, br s)

SYNTHETIC EXAMPLE 51a3-Cyano-N-(3-cyano-1H-indole-7-yl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.71 (1H, d, J=7.2 Hz), 7.09 (1H, dd, J=8.0,7.6 Hz), 7.49 (1H, d, J=8.0 Hz), 7.74 (1H, dd, J=8.0, 7.6 Hz), 7.94 (1H,d, J=8.0 Hz), 8.11-8.14 (2H, m), 8.23 (1H, d, J=2.8 Hz), 10.30 (1H, brs), 12.05 (1H, br s)

SYNTHETIC EXAMPLE 52aN-(3-Chloro-1H-indole-7-yl)-4-(N-methylmethanesusulfonamide)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

Melting point: 199 to 201° C. (decomposed) (recrystallized fromethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.98 (3H, s), 3.24 (3H, s), 6.83 (1H, dd,J=7.7, 0.37 Hz), 6.96 (1H, dd, J=7.9, 7.7 Hz), 7.26 (1H, dd, J=7.9, 0.55Hz), 7.48 (1H, d, J=2.7 Hz), 7.50-7.54 (2H, m), 7.72-7.76 (2H, m), 10.04(1H, br s), 11.02 (1H, br s)

SYNTHETIC EXAMPLE 53aN-(3-Chloro-1H-indole-7-yl)-4-[(methanesulfonamide)methyl]benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

Melting point: started coloring from the temperature close to 180° C.and decomposed at 189 to 191° C. (recrystallized from ethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.81 (3H, s), 4.19 (2H, d, J=6.0 Hz), 6.79 (1H,d, J=7.7 Hz), 6.94 (1H, dd, J=7.9, 7.7 Hz), 7.24 (1H, d, J=7.9 Hz), 7.47(2H, d, J=8.8 Hz), 7.47-7.49 (1H, m), 7.64 (1H, t, J=6.4 Hz), 7.72 (2H,d, J=8.4 Hz), 10.00 (1H, s), 11.03 (1H, br s)

SYNTHETIC EXAMPLE 54aN-(3-Chloro-1H-indole-7-yl)-4-(1-pyrrolidinylsulfonyl)benzenesulfonamide

The title compound was obtained from4-(1-pyrrolidinylsulfonyl)benzenesulfonyl chloride and the compound ofProduction Example 10a in the same manner as in Synthetic Example 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 1.55-1.59 (4H, m), 3.07-3.11 (4H, m), 6.71 (1H,d, J=7.6 Hz), 6.95 (1H, ddd, J=8.2, 7.4, 1.2 Hz), 7.30 (1H, d, J=8.0Hz), 7.46 (1H, d, J=2.4 Hz), 7.89 (2H, d, J=8.8 Hz), 7.92 (2H, d, J=8.4Hz), 10.18 (1H, br s), 11.03 (1H, br s)

SYNTHETIC EXAMPLE 55aN-(3-Cyano-1H-indole-7-yl)-1-methyl-4-imidazolesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 3.61 (3H, s), 7.00 (1H, dd, J=7.7, 0.92 Hz),7.07 (1H, dd, J=7.9, 7.7 Hz), 7.35 (1H, d, J=7.9 Hz), 7.75-7.76 (2H, m),8.19 (1H, d, J=3.1 Hz), 10.03 (1H, br s), 11.92 (1H, br s)

SYNTHETIC EXAMPLE 56aN-(3-Chloro-1H-indole-7-yl)-6-[(2-hydroxyethyl)amino]-3-pyridinesulfonamide

The title compound was obtained from the compound of Synthetic Example14a and 2-aminoethanol in the same manner as in Synthetic Example 46a.

¹H-NMR (DMSO-d₆) δ(ppm): 3.24-3.40 (2H, m), 3.42-3.52 (2H, m), 4.66-4.77(1H, m), 6.48 (1H, d, J=9.3 Hz), 6.92 (1H, d, J=7.7 Hz), 7.00 (1H, t,J=7.7 Hz), 7.24 (1H, d, J=7.7 Hz), 7.40-7.62 (2H, m), 7.48 (1H, d, J=2.2Hz), 8.22 (1H, d, J=2.6 Hz), 9.63-9.90 (1H, br), 10.90-11.07 (1H, m)

SYNTHETIC EXAMPLE 57aN-(3-Chloro-1H-indole-7-yl)-6-mercapto-3-pyridinesulfonamide

340 mg (0.99 mmol) of the compound of Synthetic Example 14a and 151 mg(1.98 mmol) of thiourea were added to 5 ml of ethanol, followed byheating under reflux for 2 hours. After concentrating, 1.6 ml of waterand 57 mg of sodium carbonate were added to the residue and theresulting mixture was stirred at room temperature for 10 minutes. 85 mgof sodium hydroxide was added thereto and the mixture was furtherstirred for 10 minutes, followed by filtering off the insoluble matters.The filtrate was acidified with hydrochloric acid, and the resultingprecipitates were collected by filtration, washed with water, thendissolved in tetrahydrofuran and dried over magnesium sulfate. Afterconcentrating, the residue was purified by silica gel thin layerchromatography, to give 121 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.84 (1H, d, J=7.6 Hz), 7.03 (1H, t, J=7.6 Hz),7.28 (1H, d, J=9.2 Hz), 7.31 (1H, d, J=7.6 Hz), 7.44 (1H, dd, J=9.2, 2.4Hz), 7.48 (1H, d, J=2.6 Hz), 7.68 (1H, d, J=2.4 Hz), 9.58-9.80 (1H, br),11.08-11.19 (1H, m)

SYNTHETIC EXAMPLE 58a7-(4-Chlorobenzenesulfonamide)-1H-indole-2-carboxylic acid

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR(DMSO-d₆) δ(ppm): 6.65 (1H, d, J=7.6 Hz), 6.87 (1H, dd, J=8.0, 7.6Hz), 7.00 (1H, s), 7.26 (1H, d, J=8.0 Hz), 7.56-7.65 (2H, m), 7.68-7.77(2H, m), 9.62-10.00 (1H, br), 11.40-11.74 (1H, br)

SYNTHETIC EXAMPLE 59aN-(3-Chloro-1H-indole-7-yl)-6-cyclopropylamino-3-pyridinesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 46a.

Melting point: started coloring from a temperature close to 228° C. anddecomposed at 233.5 to 235° C. (recrystallized from ethylacetate-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 0.36-0.46 (2H, m), 0.63-0.75 (2H, m), 2.44-2.64(1H, m), 6.45-6.64 (1H, m), 6.93 (1H, d, J=7.7 Hz), 7.00 (1H, dd, J=7.9,7.7 Hz), 7.24 (1H, d, J=7.9 Hz), 7.49 (1H, d, J=2.7 Hz), 7.57-7.73 (2H,m), 8.25 (1H, d, J=2.6 Hz), 9.68-9.90 (1H, br), 10.92-11.04 (1H, m)

SYNTHETIC EXAMPLE 60aN-(3-Cyano-1H-indole-7-yl)-5-methyl-3-pyridinesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

Melting point: gradually decomposed at a temperature close to 288° C.(recrystallized from ethanol-n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.33 (3H, s), 6.75 (1H, d, J=7.7 Hz), 7.09 (1H,dd, J=7.9, 7.7 Hz), 7.48 (1H, d, J=7.9 Hz), 7.87-7.91 (1H, m), 8.22 (1H,d, J=3.1 Hz), 8.58-8.67 (2H, m), 10.28 (1H, br s), 11.95-12.08 (1H, m)

SYNTHETIC EXAMPLE 61aN-(3-Chloro-1H-indole-7-yl)-4-(N-methylsulfamoyl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.39 (3H, d, J=5.2 Hz), 6.71 (1H, dd, J=7.8,2.0 Hz), 6.96 (1H, dd, J=8.0, 7.6 Hz), 7.30 (1H, d, J=8.0 Hz), 7.48 (1H,d, J=2.8 Hz), 7.68 (1H, q, J=4.9 Hz), 7.87-7.93 (4H, m), 10.20 (1H, brs), 11.08 (1H, br s)

SYNTHETIC EXAMPLE 62aN-(3-Chloro-1H-indole-7-yl)-4-[2-(methanesulfonamide)ethyl]benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.73-2.81 (5H, m), 3.13-3.19 (2H, m), 6.82 (1H,d, J=7.7 Hz), 6.95 (1H, dd, J=8.1, 7.7 Hz), 7.09 (1H, t, J=5.9 Hz), 7.24(1H, d, J=8.1 Hz), 7.39 (2H, d, J=8.2 Hz), 7.48 (1H, d, J=2.7 Hz), 7.68(2H, d, J=8.4 Hz), 9.97 (1H, br s), 11.02 (1H, br s)

SYNTHETIC EXAMPLE 63aN-(3-Chloro-1H-indole-7-yl)-4-(sulfamoylmethyl)benzenesulfonamide

389 mg (1.44 mmol) of the compound of Production Example 6a was reactedwith 159 mg (1.2 mmol) of the compound of Production Example 2a and thereaction product was treated in the same manner as in Example 1a, togive 233 mg of N-(1H-indole-7-yl)-4-(sulfamoylmethyl)benzenesulfonamide.The compound was chlorinated in the same manner as in Example 2a, togive 160 mg of the title compound.

Melting point: 237 to 238.5° C. (decomposed) (recrystallized fromethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 4.33 (2H, s), 6.84 (1H, dd, J=7.7, 0.73 Hz),6.93 (2H, s), 6.92-6.97 (1H, m), 7.24 (1H, dd, J=7.9, 0.37 Hz), 7.48(1H, d, J=2.7 Hz), 7.48-7.52 (2H, m), 7.75-7.79 (2H, m), 10.08 (1H, brs), 11.04 (1H, br s)

SYNTHETIC EXAMPLE 64aN-(3-Chloro-1H-indole-7-yl)-4-thiocarbamoylbenzenesulfonamide

400 mg (1.21 mmol) of the compound of Synthetic Example 10a wasdissolved in 10 ml of dimethylformamide, to which was then added 0.5 mlof triethylamine. Hydrogen sulfide was made to pass through the mixtureat a bath temperature of 60 to 70° C. for 45 minutes. Afterconcentrating, the residue was dissolved in ethyl acetate, successivelywashed with dilute hydrochloric acid, an aqueous saturated sodiumbicarbonate and water, and dried over magnesium sulfate. Afterevaporating the solvent, the residue was purified by silica gel columnchromatography, to give 355 mg of the title compound.

Melting point: 223 to 225° C. (decomposed) (recrystallized fromethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.81 (1H, d, J=7.7 Hz), 6.96 (1H, dd, J=7.9,7.7 Hz), 7.27 (1H, d, J=7.9 Hz), 7.50 (1H, d, J=2.7 Hz), 7.73-7.80 (2H,m), 7.86-7.93 (2H, m), 9.58-9.73 (1H, br m), 10.02-10.18 (1H, br m),10.15 (1H, s), 11.03-11.12 (1H, m)

SYNTHETIC EXAMPLE 65a5-Bromo-N-(3-cyano-1H-indole-7-yl)-2-pyridinesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

Melting point: 245.5 to 246.5° C. (decomposed) (recrystallized fromethyl acetate/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.82 (1H, d, J=7.7 Hz), 7.07 (1H, dd, J=7.9,7.7 Hz), 7.44 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=8.2 Hz), 8.23 (1H, d,J=2.2 Hz), 8.29 (1H, dd, J=8.2, 2.2 Hz), 8.92 (1H, d, J=2.2 Hz),10.42-10.67 (1H, br), 11.93-12.08 (1H, m)

SYNTHETIC EXAMPLE 66aN-(3-Cyano-1H-indole-7-yl)-2-naphthalenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 6.74 (1H, dd, J=7.6, 2.8 Hz), 7.00 (1H, dd,J=7.9, 7.7 Hz), 7.39 (1H, dd, J=8.0, 0.46 Hz), 7.61-7.72 (2H, m), 7.80(1H, dd, J=8.6, 1.8 Hz), 8.01 (1H, d, J=8.1 Hz), 8.08 (1H, s), 8.10 (1H,s), 8.21 (1H, d, J=2.9 Hz), 8.34 (1H, d, J=1.6 Hz), 10.23 (1H, br s),12.01 (1H, br s)

SYNTHETIC EXAMPLE 67aN-(3-Acetyl-1H-indole-7-yl)-3-chlorobenzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.44 (3H, s), 6.65 (1H, d, J=7.5 Hz), 7.01 (1H,dd, J=7.9, 7.7 Hz), 7.53-7.63 (2H, m), 7.69-7.73 (2H, m), 8.01 (1H, dd,J=8.1, 0.73 Hz), 8.26 (1H, d, J=2.9 Hz), 10.10 (1H, s), 11.75 (1H, br s)

SYNTHETIC EXAMPLE 68a4-Amino-N-(5-bromo-3-cyano-1H-indole-7-yl)benzenesulfonamide

The title compound was obtained by hydrogenatingN-(5-bromo-3-cyano-1H-indole-7-yl)-4-nitrobenzenesulfonamide, obtainedfrom 4-nitrobenzenesulfonyl chloride and the compound of ProductionExample 14a in the same manner as in Example 1a, at normal temperatureunder normal pressure in the presence of platinum oxide.

¹H-NMR (DMSO-d₆) δ(ppm): 6.07 (2H, br s), 6.52 (2H, d, J=8.4 Hz),6.97-6.99 (1H, m), 7.36 (2H, dd, J=8.7, 1.6 Hz), 7.51 (1H, br s), 8.25(1H, s), 9.93 (1H, d, J=5.5 Hz), 11.97 (1H, br s)

SYNTHETIC EXAMPLE 69aN-(3-Chloro-1H-indole-7-yl)-4-(N-ethylsulfamoyl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

Melting point: 213.5 to 215° C. (recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 0.90 (3H, t, J=7.2 Hz), 2.76 (2H, dq, Jd=5.8Hz, Jq=7.2 Hz), 6.70 (1H, d, J=7.4 Hz), 6.95 (1H, dd, J=8.0, 7.6 Hz),7.29 (1H, d, J=8.0 Hz), 7.47 (1H, d, J=2.8 Hz), 7.78 (1H, t, J=5.6 Hz),7.90 (4H, s), 10.18 (1H, br s), 11.06 (1H, br s)

SYNTHETIC EXAMPLE 70aN-(3-Chloro-1H-indole-7-yl)-4-(ethanesulfonamide)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 4a.

Melting point: 214 to 215° C. (decomposed) (recrystallized fromethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 1.14 (3H, t, J=7.3 Hz), 3.16 (2H, q, J=7.3 Hz),6.82 (1H, d, J=7.5 Hz), 6.96 (1H, dd, J=7.9, 7.7 Hz), 7.23 (2H, d, J=8.8Hz), 7.24 (1H, d, J=7.5 Hz), 7.47 (1H, d, J=2.6 Hz), 7.66 (2H, d, J=8.8Hz), 9.90 (1H, br s), 10.37 (1H, br s), 10.96 (1H, br s)

SYNTHETIC EXAMPLE 71aN-(3-Chloro-1H-indole-7-yl)-6-[(2-cyanoethyl)amino]-3-pyridinesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 46a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.72 (2H, t, J=6.4 Hz), 3.46-3.55 (2H, m), 6.53(1H, d, J=9.0 Hz), 6.90 (1H, d, J=7.7 Hz), 6.99 (1H, dd, J=7.9, 7.7 Hz),7.25 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=2.6 Hz), 7.61 (1H, dd, J=9.0, 2.4Hz), 7.78-7.87 (1H, m), 8.25 (1H, d, J=2.4 Hz), 9.70-9.95 (1H, br),10.92-11.04 (1H, m)

SYNTHETIC EXAMPLE 72aN-(3-Chloro-1H-indole-7-yl)-4-(N-methylcarbamoyl)benzenesulfonamide

533 mg (1.68 mmol) of the compound of Synthetic Example 9a was dissolvedin a mixed solution of 5 ml of dimethylformamide and 2.5 ml of dimethylsulfoxide, to which were then added 171 mg (2.53 mmol) of methylaminehydrochloride and 705 μl (5.06 mmol) of triethylamine. 436 μl (2.02mmol) of diphenylphosphrylazide was added thereto, followed by stirringat room temperature overnight. Then, the mixture was concentrated andextracted with ethyl acetate. The extract was successively washed withdilute hydrochloric acid, an aqueous saturated sodium bicarbonate andwater, and dried over magnesium sulfate. After concentrating, theresidue was purified by silica gel column chromatography, to give 465 mgof N-(1H-indole-7-yl)-4-(N-methylcarbamoyl)benzenesulfonamide. Theobtained compound was chlorinated in the same manner as in SyntheticExample 2a, to give 413 mg of the title compound.

Melting point: 252 to 253° C. (decomposed) (recrystallized fromethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.76 (3H, d, J=4.6 Hz), 6.74 (1H, d, J=7.7 Hz),6.94 (1H, dd, J=7.9, 7.7 Hz), 7.27 (1H, d, J=7.9 Hz), 7.49 (1H, d, J=2.7Hz), 7.76-7.83 (2H, m), 7.87-7.94 (2H, m), 8.61 (1H, q, J=4.6 Hz), 10.10(1H, s), 11.03-11.13 (1H, m)

SYNTHETIC EXAMPLE 73aN-(3-chloro-1H-indole-7-yl)-4-(methylsulfonylmethyl)benzenesulfonamide

510 mg of the compound of Synthetic Example 34a was oxidized usingaqueous 30% hydrogen peroxide in the same manner as in Example 23a, togive 307 mg of the title compound.

Melting point: started coloring from a temperature close to 225° C. anddecomposed gradually from a temperature close to 235° C. (recrystallizedfrom ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 2.88 (3H, s), 4.57 (2H, s), 6.77 (1H, d, J=7.6Hz), 6.94 (1H, dd, J=7.9, 7.7 Hz), 7.25 (1H, d, J=8.0 Hz), 7.47 (1H, d,J=2.7 Hz), 7.51-7.56 (2H, m), 7.73-7.78 (2H, m), 10.05 (1H, br s), 11.04(1H, br s)

SYNTHETIC EXAMPLE 74aN-(3-Chloro-1H-indole-7-yl)-4-(N,N-dimethylsulfamoyl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.57 (6H, s), 6.71 (1H, dd, J=7.4, 0.6 Hz),6.97 (1H, dd, J=8.0, 7.6 Hz), 7.31 (1H, d, J=8.0 Hz), 7.47 (1H, d, J=2.8Hz), 7.86 (2H, d, J=8.4 Hz), 7.91 (2H, d, J=8.4 Hz), 10.19 (1H, br s),11.04 (1H, br s)

SYNTHETIC EXAMPLE 75aN-(3-Chloro-1H-indole-7-yl)-4-(1-pyrrolidinylcarbonyl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 1.79 (2H, dt, Jd=12.8 Hz, Jt=6.4 Hz), 1.85 (2H,dt, Jd=13.6 Hz, Jt=6.8 Hz), 3.22 (2H, t, J=6.4 Hz), 3.44 (2H, t, J=6.8Hz), 6.78 (1H, d, J=7.2 Hz), 6.96 (1H, dd, J=8.0, 7.2 Hz), 7.28 (1H, d,J=8.0 Hz), 7.47 (1H, d, J=2.4 Hz), 7.60 (2H, d, J=8.0 Hz), 7.74 (2H, d,J=8.4 Hz), 10.06 (1H, br s), 11.01 (1H, br s)

SYNTHETIC EXAMPLE 76a3-Chloro-N-(3-chloro-1H-indole-7-yl)-N-methylbenzenesulfonamide

120 mg (0.352 mmol) of the compound of Synthetic Example 7a wasdissolved in 10 ml of dimethylformamide, to which was then added 19.2 mg(0.479 mmol) of sodium hydride (60%). After stirring at room temperaturefor 30 minutes, 30 μl (0.482 mmol) of methyl iodide was added thereto.After two hours, water was added thereto, followed by extracting withethyl acetate. The organic layer was washed with water and dried overmagnesium sulfate. After concentrating, the residue was purified bysilica gel thin layer chromatography, to give 87 mg of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 3.26 (3H, s), 6.51 (1H, dd, J=7.6, 0.64 Hz),7.00 (1H, dd, J=7.9, 7.7 Hz), 7.47 (1H, d, J=8.1 Hz), 7.53 (1H, d, J=2.7Hz), 7.54-7.59 (2H, m), 7.65 (1H, t, J=7.9 Hz), 7.84 (1H, ddd, J=8.1,2.1, 1.1 Hz), 11.62 (1H, br s)

SYNTHETIC EXAMPLE 77aN-(3,4-Dichloro-1H-indole-7-yl)-4-(sulfamoylmethyl)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

Melting point: decomposed gradually from a temperature close to 297° C.(recrystallized from ethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 4.34 (2H, s), 6.72 (1H, d, J=8.1 Hz), 6.93 (2H,s), 6.94 (1H, d, J=8.1 Hz), 7.51 (2H, d, J=8.1 Hz), 7.57 (1H, dd, J=2.7,0.55 Hz), 7.75 (2H, d, J=8.2 Hz), 10.10 (1H, br s), 11.44 (1H, br s)

SYNTHETIC EXAMPLE 78aN-(3-Cyano-1H-indole-7-yl)-4-[2-(methylsulfonyl)ethyl]benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExample 1a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.94 (3H, s), 3.03-3.08 (2H, m), 3.42-3.47 (2H,m), 6.77 (1H, dd, J=7.7, 0.37 Hz), 7.05 (1H, t, J=7.9 Hz), 7.41 (1H, d,J=8.1 Hz), 7.46 (2H, d, J=8.2 Hz), 7.66 (2H, d, J=8.2 Hz), 8.20 (1H, s),10.09 (1H, br s), 11.92 (1H, br s)

SYNTHETIC EXAMPLE 79aN-(3-Chloro-1H-indole-7-yl)-4-(N-methylacetamido)benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 1.84 (3H, br s), 3.16 (3H, s), 6.81 (1H, d,J=7.7 Hz), 6.96 (1H, dd, J=8.0, 7.6 Hz), 7.27 (1H, d, J=7.9 Hz),7.45-7.49 (2H, m), 7.47 (1H, d, J=2.7 Hz), 7.70-7.75 (2H, m), 10.02 (1H,br s), 11.01 (1H, br s)

SYNTHETIC EXAMPLE 80aN-(3-Chloro-1H-indole-7-yl)-6-hydroxy-3-pyridinesulfonamide

Under ice-cooling, into a solution of the compound of Example 33a (100mg, 0.31 mmol) dissolved in 2 ml of glacial acetic acid was addeddropwise 1 ml of an aqueous solution containing 32 mg (0.46 mmol) ofsodium nitrite. After stirring for one hour, the mixture was adjusted toabout pH 8 by adding an aqueous sodium bicarbonate and further stirredfor 10 minutes. The reaction mixture was extracted with ethyl acetate,and the extract was washed with water, dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gel thin layerchromatography, to give 54 mg of the title compound.

Melting point: 244-245° C. (decomposed) (recrystallized from ethylacetate/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 6.39 (1H, d, J=9.5 Hz), 6.88 (1H, d, J=7.7 Hz),7.04 (1H, dd, J=7.9, 7.7 Hz), 7.32 (1H, d, J=7.9 Hz), 7.50 (1H, d, J=2.7Hz), 7.58 (1H, dd, J=9.5, 3.1 Hz), 7.64 (1H, d, J=3.1 Hz), 9.76-9.94(1H, br), 11.01-11.13 (1H, m), 11.98-12.15 (1H, br)

SYNTHETIC EXAMPLE 81aN-(3-Chloro-1H-indole-7-yl)-4-[2-(N-methylmethanesulfonamido)ethyl]benzenesulfonamide

The title compound was obtained in the same manner as in SyntheticExamples 1a and 2a.

¹H-NMR (DMSO-d₆) δ(ppm): 2.69 (3H, s), 2.76 (3H, s), 2.86 (2H, t, J=7.5Hz), 3.26 (2H, t, J=7.5 Hz), 6.78 (1H, dd, J=7.4, 0.55 Hz), 6.94 (1H, t,J=7.7 Hz), 7.24 (1H, dd, J=7.7, 0.37 Hz), 7.39 (2H, d, J=8.2 Hz), 7.48(1H, d, J=2.6 Hz), 7.66 (2H, d, J=8.2 Hz), 9.94 (1H, br s), 11.02 (1H,br s)

SYNTHETIC EXAMPLE 82aN-(3-Chloro-1H-indole-7-yl)-4-(trifluoromethanesulfonamido)benzenesulfonamide

128 μl (0.76 mmol) of trifluoromethanesulfonic acid anhydride was addedto a pyridine solution (5 ml) containing 62 mg (0.19 mmol) of thecompound of Synthetic Example 3a at 0° C., followed by stirring as itwas overnight. The reaction solution was evaporated. A phosphoric acidbuffer solution having a pH of 7 was added thereto, followed byextracting with ethyl acetate. Then, the extract was washed with brineand dried over magnesium sulfate. The solvent was evaporated and theresidue was purified by silica gel column chromatography, to give 20 mgof the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.79 (1H, d, J=7.7 Hz), 6.94 (1H, dd, J=7.9,7.7 Hz), 7.16 (2H, d, J=8.6 Hz), 7.23 (1H, d, J=7.9 Hz), 7.46 (1H, d,J=2.7 Hz), 7.58 (2H, d, J=8.1 Hz), 9.84 (1H, br s), 10.98 (1H, br s)

SYNTHETIC EXAMPLE 83aN-(3-Chloro-1H-indole-7-yl)-4-[(N-methylmethanesulfonamido)methyl]benzenesulfonamide

The title compound was obtained in the same manner as in Syntheticexamples 1a and 2a.

Melting point: 200.5 to 202° C. (recrystallized from ethanol)

¹H-NMR (DMSO-d₆) δ(ppm): 2.63 (3H, s), 2.94 (3H, s), 4.27 (2H, s), 6.80(1H, d, J=7.3 Hz), 6.95 (1H, dd, J=8.1, 7.5 Hz), 7.25 (1H, d, J=7.9 Hz),7.45 (2H, d, J=8.2 Hz), 7.47 (1H, d, J=2.7 Hz), 7.74 (2H, d, J=8.2 Hz),10.00 (1H, s), 11.00 (1H, br s)

SYNTHETIC EXAMPLE 84a3-Chloro-N-(3-chloro-1H-pyrrolo[2,3-c]pyridine-7-yl)-benzenesulfonamide

To 84 ml of aqueous concentrated ammonia were added 600 mg (3.05 mmol)of 7-bromo-1H-pyrrolo[2,3-c]pyridine synthesized from2-bromo-3-nitropyridine in the same manner as in Production Example 1a,194 mg of a copper powder and 603 mg of cuprous chloride. The mixturewas heated in a sealed tube at 120° C. for 15 hours and then treated, togive 170 mg of 7-amino-1H-pyrrolo[2,3-c]pyridine. The resulting productwas reacted and treated in the same manner as in Examples 1a and 2a, togive 57 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.93 (1H, d, J=6.6 Hz), 7.45 (1H, dd, J=6.6,5.8 Hz), 7.53 (1H, dd, J=8.0, 7.6 Hz), 7.61 (1H, d, J=7.6 Hz), 7.73 (1H,d, J=2.8 Hz), 7.85 (1H, d, J=8.0 Hz), 7.96 (1H, d, J=1.2 Hz),11.90-12.10 (1H, m), 12.72 (1H, br s)

SYNTHETIC EXAMPLE 85aN-(3-Chloro-1H-indole-7-yl)-4-[3-(1-imidazolyl)propyl]benzenesulfonamide

To 4-(3-bromopropyl)-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide (213mg, 0.5 mmol) were added 170 mg (2.5 mmol) of imidazole and 6 ml ofdimethylformamide, followed by heating at 80° C. for 3 hours in anitrogen atmosphere. Then, the reaction mixture was poured into waterand extracted with chloroform. The extract was dried over magnesiumsulfate and concentrated. Then, the residue was purified by silica gelcolumn chromatography, to give 160 mg of the title compound.

Melting point: 86 to 90° C.

¹H-NMR (DMSO-d₆) δ(ppm): 1.95-2.04 (2H, m), 2.55 (2H, t, J=7.9 Hz), 3.92(2H, t, J=7.1 Hz), 6.81 (1H, dd, J=7.7, 0.9 Hz), 6.88 (1H, t, J=1.1 Hz),6.94 (1H, dd, J=7.9, 7.7 Hz), 7.16 (1H, t, J=1.2 Hz), 7.23 (1H, d, J=7.7Hz), 7.32 (2H, d, J=8.4 Hz), 7.47 (1H, d, J=2.7 Hz), 7.60 (1H, br s),7.65 (2H, d, J=8.4 Hz), 9.91-10.01 (1H, m), 10.98-11.02 (1H, m)

SYNTHETIC EXAMPLE 86aN-(3-Chloro-1H-indole-7-yl)-4-[N-[2-(2-pyridinyl)ethyl]carbamoyl]benzenesulfonamide

2.82 g (12.8 mmol) of 4-(chlorosulfonyl)benzoic acid and 1.42 g (8.54mmol) of 7-amino-3-chloro-1H-indole were reacted with each other inpyridine at room temperature under stirring overnight, to give 2.33 g of4-[N-(3-chloro-1H-indole-7-yl)sulfamoyl]benzoic acid. To 303 mg (0.86mmol) of the product were successively added 260 μl ofdimethylformamide, 204 μl (0.95 mmol) of diphenylphosphorylazide, 132 μl(0.95 mmol) of triethylamine and 113 μl (0.94 mmol) of2-(2-aminoethyl)pyridine, followed by stirring at room temperatureovernight. After concentrating, ethyl acetate and an aqueous saturatedsodium bicarbonate were added thereto. The organic layer was separatedand washed with brine. After evaporating the solvent, the residue waspurified by silica gel column chromatography, to give 175 mg of thetitle compound.

Melting point: 220.5 to 222° C.

¹H-NMR (DMSO-d₆) δ(ppm): 2.95-2.99 (2H, m), 3.56-3.62 (2H, m), 6.75 (1H,d, J=7.5 Hz), 6.94 (1H, dd, J=7.9, 7.7 Hz), 7.19-7.28 (3H, m), 7.48 (1H,d, J=2.8 Hz), 7.69 (1H, dt, Jd=1.8 Hz, Jt=7.7 Hz), 7.79 (2H, d, J=8.6Hz), 7.88 (2H, d, J=8.6 Hz), 8.48-8.51 (1H, m), 8.75 (1H, t, J=5.2 Hz),10.09-10.12 (1H, m), 11.06-11.09 (1H, m)

SYNTHETIC EXAMPLE 87a4-Amidino-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide

3.3 ml (3.3 mmol) of a hexane solution containing 1.0 Mtrimethylaluminum and 10 ml of toluene were added to 162 mg (3.0 mmol)of ammonium chloride. After the generation of gas was ceased, themixture was evaporated until the amount of the solution became about 3ml. While stirring, 97 mg (0.30 mmol) of the compound of ProductionExample 4a was added thereto and the mixture was heated at 80° C. for 4hours. After cooling, a concentrated ammonia was added thereto, theinsoluble matters were filtered off and the filtrate was concentrated.Ethyl acetate was added thereto, the insoluble matters were filtered offand the filtrate was concentrated. The residue was purified by silicagel column chromatography, to give 35 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.93 (1H, dd, J=7.7, 1.5 Hz), 6.96 (1H, dd,J=7.7, 7.5 Hz), 7.24 (1H, dd, J=7.5, 1.3 Hz), 7.50 (1H, d, J=2.7 Hz),7.90 (2H, d, J=8.6 Hz), 8.01 (2H, d, J=8.6 Hz), 9.16-9.62 (2H, br),10.40-10.75 (1H, br), 11.50 (1H, s)

SYNTHETIC EXAMPLE 88aN-(3-Chloro-1H-indole-7-yl)-4[N-[2-(1-imidazolyl)ethyl]sulfamoyl]benzenesulfonamide

557 mg (1.13 mmol) of4-[N-(2-bromoethyl)sulfamoyl]-N-(3-chloro-1H-indole-7-yl)benzenesulfonamideand 820 mg (12.0 mmol) of imidazole were added to 10 ml ofdimethylformamide and the mixture was stirred at 80° C. for 2 days.After concentrating, the residue was dissolved in ethyl acetate. Themixture was washed with water, dried over sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography, to give 324 mg of the title compound.

Melting point: started coloring gradually from a temperature close to200° C. and decomposed at 218 to 221° C. (recrystallized fromethanol/n-hexane)

¹H-NMR (DMSO-d₆) δ(ppm): 3.05 (2H, ddd, J=6.2, 6.0, 5.9 Hz), 3.96 (2H,dd, J=6.0, 5.9 Hz), 6.69-6.72 (1H, m), 6.84 (1H, br s), 6.92 (1H, dd,J=7.9, 7.7 Hz), 7.08 (1H, br s), 7.26 (1H, d, J=7.5 Hz), 7.44 (1H, d,J=2.7 Hz), 7.55 (1H, br s), 7.82-7.88 (4H, m), 8.06 (1H, t, J=5.9 Hz),10.18-10.36 (1H, br), 11.09 (1H, d, J=2.4 Hz)

SYNTHETIC EXAMPLE 89a3-(5-Bromonicotinamido)-N-(3-cyano-1H-indole-7-yl)benzenesulfonamide

785 mg (3.54 mmol) of 3-nitrobenzenesulfonyl chloride was reacted with506 mg (3.22 mmol) of the compound of Production Example 3a in the samemanner as in Production Example 4a and treated, to give 950 mg ofN-(3-cyano-1H-indole-7-yl)-3-nitrobenzenesulfonamide. The product wasreduced using zinc powder/concentrated hydrochloric acid in 30 ml ofmethanol according to a conventional method, to give 459 mg of3-amino-N-(3-cyano-1H-indole-7-yl)benzenesulfonamide. 109 mg (0.35 mmol)of the product was dissolved in 2 ml of pyridine and 179 mg (0.70 mmol)of 5-bromonicotinoyl chloride hydrochloride was added thereto. Afterstirring at room temperature overnight, the mixture was concentrated. Anaqueous diluted citric acid was added to the residue. The resultingprecipitates were collected by filtration, and successively washed withwater, an aqueous diluted sodium bicarbonate, water and ether. Theprecipitates were dissolved in tetrahydrofuran, and the mixture wasdried over magnesium sulfate and concentrated. Crystals precipitated byadding ether and n-hexane were collected by filtration, to give 108 mgof the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.81 (1H, dd, J=7.7, 0.7 Hz), 7.07 (1H, t,J=7.9 Hz), 7.42 (1H, dd, J=7.9, 0.7 Hz), 7.47-7.51 (1H, m), 7.55 (1H, t,J=7.9 Hz), 7.93-7.97 (1H, m), 8.21-8.23 (1H, m), 8.31 (1H, t, J=1.8 Hz),8.55 (1H, dd, J=2.4, 2.0 Hz), 8.93 (1H, d, J=2.4 Hz), 9.06 (1H, d, J=2.0Hz), 10.23-10.25 (1H, m), 10.75 (1H, br s), 11.94-11.96 (1H, m)

SYNTHETIC EXAMPLE 90aN-(3-Chloro-1H-indole-7-yl)-4[N-(2-thiazolyl)sulfamoyl]-benzenesulfonamide

5.2 g (20.4 mmol) of sulfathiazole was added to a mixed solution of 14ml of water and 3.4 ml of concentrated hydrochloric acid and the mixturewas stirred. To the mixture was added dropwise an aqueous saturatedsolution of 2.1 g (30.4 mmol) of sodium nitrite at 0° C. or less. Then,5 ml of acetic acid was added thereto, followed by stirring at 5° C. forabout 10 minutes. An acetic acid solution saturated with sulfur dioxide(solution prepared by saturating 18 ml of acetic acid with sulfurdioxide and then adding 830 mg of cupric chloride.dihydrate thereto) wasadded dropwise to the reaction solution at 0° C. under stirring. After 5minutes, the reaction solution was poured into ice-water. Theprecipitates were collected by filtration, washed with water and dried,to give 2.9 g of 4-chlorosulfonyl-N-(2-thiazolyl)benzenesulfonamide. 570mg (1.68 mmol) of the product was reacted with 200 mg (1.2 mmol) of thecompound of Production Example 1a in the same manner as in ProductionExample 4a and treated, to give 456 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 6.68 (1H, dd, J=7.5, 0.73 Hz), 6.87 (1H, d,J=4.6 Hz), 6.93 (1H, dd, J=8.1, 7.5 Hz), 7.26-7.30 (1H, m), 7.28 (1H, d,J=4.6 Hz), 7.46 (1H, d, J=2.7 Hz), 7.82-7.88 (2H, m), 7.88-7.94 (2H, m),10.10-10.26 (1H, br), 11.04-11.10 (1H, m), 12.83-13.01 (1H, br)

SYNTHETIC EXAMPLE 91a5-Chloro-N-(3-chloro-1H-indole-7-yl)-4-(5-methyl-3-pyridinesulfonamido)-2-thiophenesulfonamide

645 mg (2.46 mmol) of 5-chloro-4-nitro-2-thiophenesulfonyl chloride wasreacted with 410 mg (2.46 mmol) of the compound of Production Example 1ain the same manner as in Production Example 4a and treated, to give 194mg of5-chloro-N-(3-chloro-1H-indole-7-yl)-4-nitro-2-thiophenesulfonamide. Theproduct was reduced using zinc powder/concentrated hydrochloric acid in10 ml of methanol according to a conventional method, to give 75 mg of4-amino-5-chloro-N-(3-chloro-1H-indole-7-yl)-2-thiophenesulfonamide. 72mg (0.20 mmol) of the product was dissolved in 2 ml of tetrahydrofuran,and 18 μl of pyridine and 38 mg (0.2 mmol) of5-methyl-3-pyridinesulfonyl chloride were added thereto. After stirringat room temperature overnight, the organic layer was separated by addingethyl acetate and 1N hydrochloric acid thereto. It was successivelywashed with water, an aqueous sodium bicarbonate and water, dried overmagnesium sulfate and concentrated. Then, the residue was purified bysilica gel column chromatography, to give 82 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.33 (3H, s), 6.76 (1H, d, J=7.7 Hz), 7.03 (1H,dd, J=7.9, 7.7 Hz), 7.35 (1H, s), 7.38 (1H, d, J=7.9 Hz), 7.51 (1H, d,J=2.7 Hz), 7.80 (1H, dd, J=2.0, 1.5 Hz), 8.60 (1H, dd, J=2.0, 0.4 Hz),8.71 (1H, dd, J=1.5, 0.4 Hz), 10.35-10.40 (1H, m), 10.73-10.80 (1H, br),11.16-11.19 (1H, m)

PRODUCTION EXAMPLE 1b 2-Amino-5-bromoquinoline

2-Bromo-6-nitrobenzaldehyde (30.4 g), magnesium oxide (75 g) anddimethyl sulfoxide (11.3 ml) were sufficiently stirred for one minute.Then, to the mixture was added diethyl (cyanomethyl)phosphonate (25.8ml) and the mixture was stirred for further 2 hours. The stirring wasstopped and the reaction mixture was allowed to stand overnight.Thereafter, ethyl acetate was added thereto and the resulting mixturewas stirred, followed by filtering. The filtrate was concentrated andthe residue was purified by silica gel column chromatography (ethylacetate), to give 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (Eisomer:Z isomer=3:1).

¹H-NMR (CDCl₃) δ(ppm): 5.63 (d, J=16.5 Hz, E-isomer 1H), 5.81 (d, J=10.8Hz, Z-isomer 1H), 7.42-7.52 (m, E-isomer 1H, Z-isomer 2H), 7.56 (d,J=16.5 Hz, E-isomer 1H), 7.90-8.16 (m, E-isomer 2H, Z-isomer 2H).

Next, ethanol (250 ml), tin (60 g) and distilled water (150 ml) wereadded to 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E isomer:Zisomer=3:1), followed by heating under stirring at 90° C. To the mixturewas added dropwise concentrated hydrochloric acid (256 ml), followed bystirring at the same temperature for 3 hours. After returning to roomtemperature, the liquid layer was decanted and cooled to 0° C. Theresulting solid was collected by filtration. An aqueous ammonia wasadded thereto, and the mixture was extracted by ethyl acetate. Theextract was concentrated and the residue was purified by silica gelcolumn chromatography (ethyl acetate), to give 5.0 g of the titlecompound.

¹H-NMR (CDCl₃) δ(ppm): 4.88 (2H, bs), 6.79 (1H, d, J=9.3 Hz), 7.39 (1H,t, J=8.9 Hz), 7.51 (1H, d, J=8.9 Hz), 7.61 (1H, d, J=8.9 Hz), 8.27 (1H,d, J=9.3 Hz).

PRODUCTION EXAMPLE 2b 2-Amino-5-chloroquinoline

The title compound was obtained from 2-chloro-6-nitrobenzaldehyde in thesame manner as in Production Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 5.25 (2H, bs), 6.80 (1H, d, J=9.7 Hz), 7.32 (1H,dd, J=7.5 Hz, 1.5 Hz), 7.46 (1H, t, J=7.5 Hz), 7.57 (1H, m), 8.30 (1H,d, J=9.7 Hz, 1.0 Hz).

PRODUCTION EXAMPLE 3b 3-Carbethoxy-4-hydroxy-8-bromoquinoline

A mixture of 50 g (0.291 mol) of 2-bromoaniline and 63 g (0.291 mol) ofdiethylethoxymethylene malonate was heated at 100° C. under reducedpressure for 3 hours and further at 200° C. for 12 hours. After thereaction was completed, the reaction mixture solid was washed with ethylacetate and the crystals were collected by filtration and dried, to give50 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.26 (3H, t, J=7.2 Hz), 4.21 (2H, q, J=7.2 Hz),7.34 (1H, t, J=7.6 Hz), 8.03 (1H, dd, J=1.6 Hz, 7.6 Hz), 8.15 (1H, dd,J=1.6 Hz, 7.6 Hz), 8.43 (1H, s), 11.56 (1H, s).

PRODUCTION EXAMPLE 4b 3-Carbethoxy-8-bromoquinoline

A mixture of 2.5 g (8.4 mmol) of 3-carbethoxy-4-hydroxy-8-bromoquinolineand 10 ml of phosphorous oxychloride was heated under reflux for onehour. After the reaction was completed, phosphorous oxychloride wasremoved and the residue was purified by NH silica gel, to give 2.6 g ofa chloro-compound. Next, 500 mg (1.6 mmol) of the chloro-compound wasdissolved in 20 ml of dioxane, 1 g of zinc powder and 3 ml of aceticacid were added thereto, followed by heating at 65° C. for 30 minutes.Ethyl acetate was added to the reaction solution, and the mixture wasfiltered through Celite. The filtrate was washed with brine, dried overmagnesium sulfate and concentrated. To the residue was added 1 ml ofacetic acid, and the mixture was allowed to stand for 12 hours and thenacetic acid was removed. The residue was subjected to silica gel columnchromatography, and eluted with the solvent (ethylacetate/n-hexane=1/7), to give obtaining 180 mg of the title compound.

¹H-NMR (CDCl₃) δ(ppm): 1.47 (3H, t, J=7.2 Hz), 4.50 (2H, q, J=7.2 Hz),7.50 (1H, t, J=7.6 Hz), 7.93 (1H, dd, J=1.2 Hz, 7.6 Hz), 8.18 (1H, dd,J=1.2 Hz, 7.6 Hz), 8.85 (1H, d, J=2 Hz), 9.57 (1H, d, J=2 Hz).

PRODUCTION EXAMPLE 5b 3-Amino-8-bromoquinoline

500 mg (1.8 mmol) of 3-carbethoxy-8-bromoquinoline was added to anaqueous ethanol (10 ml)/1 N NaOH solution (10 ml) and the mixture wasstirred at room temperature for 3 hours. Ethanol was removed and theresidue was neutralized with 1N HCl. The resulting solid was collectedby filtration, washed with water and dried, to give 450 mg of acarboxylic acid. Next, 450 mg (1.8 mmol) of the carboxylic acid wasadded to 25 ml of tert-butanol. Further, to the mixture were added 0.58ml (2.7 mmol) of DPPA and 0.37 ml (2.7 mmol) of triethylamine, followedby heating under reflux for 12 hours. The reaction solution wasconcentrated, and the residue was subjected to silica gel chromatographyand eluted with the solvent (ethyl acetate-n-hexane=1-4), to give 352 mgof an amide compound. Next, 350 mg (1.1 mmol) of the amide compound wasadded to a mixed solution of 4 ml of methanol/2 ml of conc. HCl, and themixture was stirred at room temperature for one hour. The reactionsolution was basified with an aqueous ammonia and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and then concentrated, to give 240 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 5.88 (2H, s), 7.13 (1H, d, J=2.8 Hz), 7.24 (1H,dd, J=7.6 Hz, 8.4 Hz), 7.59-7.65 (2H, m), 8.49 (1H, d, J=2.8 Hz).

PRODUCTION EXAMPLE 6b 3-Amino-8-iodoquinoline

The title compound was obtained from 2-iodoaniline in the same manner asin Production Examples (3b-5b).

¹H-NMR (DMSO-d₆) δ(ppm): 5.85 (2H, s), 7.07 (1H, d, J=2.8 Hz), 7.10 (1H,t, J=7.6 Hz), 7.62 (1H, dd, J=1.2 Hz, 7.6 Hz), 7.90 (1H, dd, J=1.2 Hz,7.6 Hz), 8.45 (1H, d, J=2.8 Hz).

PRODUCTION EXAMPLE 7b 3-Amino-8-cyanoquinoline

The title compound was obtained from 2-cyanoaniline in the same manneras in Production Examples (3b-5b).

¹H-NMR (DMSO-d₆) δ(ppm): 6.03 (2H, br s), 7.22 (1H, d, J=2.8 Hz), 7.48(1H, dd, J=7.2 Hz, 8.4 Hz), 7.84 (1H, dd, J=1.2 Hz, 8.4 Hz), 7.94 (1H,dd, J=1.2 Hz, 8.4 Hz), 8.57 (1H, d, J=2.8 Hz).

PRODUCTION EXAMPLE 8b 3-Amino-8-(methylsulfonyl)quinoline

The title compound was obtained in the same manner as in ProductionExamples (3b-5b).

¹H-NMR (CDCl₃) δ(ppm): 6.00 (2H, s), 7.26 (1H, d, J=2.4 Hz), 7.53 (1H,t, J=7.2 Hz), 7.91 (1H, dd, J=1.6 Hz, 7.2 Hz), 7.96 (1H, dd, J=1.2 Hz,8.4 Hz), 8.58 (1H, d, J=2.8 Hz).

PRODUCTION EXAMPLE 9b 3-Amino-8-chloroquinoline

The title compound was obtained in the same manner as in ProductionExamples (3b-5b).

¹H-NMR (DMSO-d₆) δ(ppm): 5.90 (2H, s), 7.17 (1H, d, J=2.8 Hz), 7.33 (1H,t, J=7.6 Hz), 7.46 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=7.6 Hz), 8.52 (1H,d, J=2.8 Hz).

PRODUCTION EXAMPLE 10b 3-Amino-8-trifluoromethylquinoline

The title compound was obtained in the same manner as in ProductionExamples (3b-5b).

¹H-NMR (DMSO-d₆) δ(ppm): 5.94 (2H, s), 7.23 (1H, d, J=2.8 Hz), 7.48 (1H,t, J=7.6 Hz), 7.69 (1H, d, J=7.6 Hz), 7.91 (1H, d, J=7.6 Hz), 8.55 (1H,d, J=2.8 Hz).

PRODUCTION EXAMPLE 11b Ethyl-8-chloro-4-vinylquinoline-3-carboxylate

Tributylvinyltin (2.8 ml) and tetrakistriphenylphosphinepalladium (171mg) were added to a toluene solution (20 ml) containing 2.0 g (7.4 mmol)of ethyl-4,8-dichloroquinoline-3-carboxylate obtained in the same manneras in Production Example 4b, followed by stirring for 2 hours underheating under reflux. The reaction solution was filtered through Celiteand the filtrate was concentrated. Then, the residue was purified bysilica gel chromatography, to give 1.92 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.36 (3H, t, J=7.6 Hz), 4.37 (2H, d, J=7.6 Hz),5.52 (1H, d, J=18.0 Hz), 5.58 (1H, d, J=16.4 Hz), 7.40 (1H, dd, J=16.4,18.0 Hz), 7.70 (1H, t, J=8.0 Hz), 8.11 (1H, d, J=8.0 Hz), 8.25 (1H, d,J=8.0 Hz), 9.24 (1H, s).

PRODUCTION EXAMPLE 12b 3-Amino-8-chloro-4-vinylquinoline

The title compound was obtained fromethyl-4-vinyl-8-chloroquinoline-3-carboxylate in the same manner as inProduction Example 5b.

¹H-NMR (DMSO-d₆) δ(ppm): 5.69 (1H, dd, J=1.6, 18.0 Hz), 5.81 (2H, s),5.84 (1H, dd, J=1.6, 11.6 Hz), 6.91 (1H, dd, J=11.6, 18.0 Hz), 7.38 (1H,t, J=8.0 Hz), 7.52 (1H, dd, J=1.2, 8.0 Hz), 7.85 (1H, dd, J=1.2, 8.0Hz), 8.60 (1H, s).

PRODUCTION EXAMPLE 13b Ethyl-7-amino-2-chloroquinoline-4-carboxylate

43 g (231 mmol) of diethyl oxaloacetate was added to 25 g (231 mmol) ofmethaphenylenediamine and the mixture was stirred at 160° C. for onehour. After cooling as it was, the crystals were washed with methanol.Phosphorous oxychloride (3.6 ml) was added to a chloroform solution (30ml) containing 3.0 g (13 mmol) of the crystals, followed by heatingunder reflux for one hour. After cooling as it was, the mixture waspoured into ice-water and basified with a 1 N aqueous sodium hydroxide.Then, crystals were collected by filtration and washed withtetrahydrofuran, and the filtrate was evaporated, to give 4.85 g of thetitle compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.31-1.42 (3H, m), 4.34-4.46 (2H, m), 6.92 (1H,d, J=2.4 Hz), 7.12 (1H, dd, J=2.4, 9.2 Hz), 7.40 (1H, s), 8.21 (1H, d,J=9.2 Hz).

PRODUCTION EXAMPLE 14b 2-Benzylthio-4-methoxypyridazine

843 mg (21 mmol, 55% oily) of sodium hydride was suspended in dimethylsulfoxide (30 ml). Under ice-cooling, 2.0 ml (16.7 mmol) ofbenzylmercaptan was added thereto, followed by stirring for 10 minutes.To the reaction mixture was added 2.5 g (17.6 mmol) of4-methoxy-2-chloropyridazine, followed by stirring at room temperatureovernight. To the reaction mixture was added an aqueous saturatedammonium chloride, followed by extracting with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gelchromatography, to give 1.63 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 3.98 (3H, s), 4.48 (2H, s), 7.12 (1H, d, J=8.8Hz), 7.22-7.26 (1H, m), 7.29-7.37 (2H, m), 7.41-7.44 (2H, m), 7.57 (1H,d, J=8.8 Hz).

PRODUCTION EXAMPLE 15b 2-Benzylthio-4-carboxyamidopyridine

Thionyl chloride (120 ml) was added to 25 g (159 mmol) of2-chloroisonicotinic acid, and the mixture was stirred while heatingunder reflux for 3 hours. After cooling as it was, the mixture wasevaporated, to give the residue. A tetrahydrofuran solution (200 ml)containing the reside was poured into a mixed solution of an aqueousammonium (200 ml) and a tetrahydrofuran (200 ml) under ice-cooling.After stirring under ice-cooling for 15 minutes, the mixture wasevaporated. Crystals were collected by filtration and washed with water,to give 22.6 g of white crystals. 4.2 ml (36 mmol) ofbenzylthiomercaptan and 10 g (77 mmol) of potassium carbonate were addedto a dimethylformamide solution containing 5.13 g (32 mmol) of the whitecrystals, and the mixture was stirred while heating under reflux for 3hours. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and evaporated. Then, the residue waspurified by silica gel chromatography, and the resulting crystals werewashed with hexane, to give 6.3 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 4.46 (2H, s), 7.22-7.33 (3H, m), 7.41 (2H, d,J=7.2 Hz), 7.49 (1H, dd, J=1.6, 5.2 Hz), 7.67 (1H, s), 7.73 (1H, s),8.21 (1H, s), 8.58 (1H, d, J=5.2 Hz).

PRODUCTION EXAMPLE 16b 7-Amino-2-chloro-4-methylquinoline

32 ml (251 mmol) of ethyl acetoacetate was added to 27 g (251 mmol) ofmethaphenylenediamine and the mixture was stirred at 200° C. for onehour. After cooling as it was, crystals were washed with hexane. 15 mlof phosphorous oxychloride was added to 9.5 g (54 mmol) of the crystals,followed by heating under reflux for 2 hours. After cooling as it was,the reaction mixture was poured into ice-water and basified with anaqueous saturated ammonium. The resulting crystals were collected byfiltration and washed with water. The crystals were washed with methanoland the filtrate was evaporated, to give 4.85 g of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 3.18 (3H, s), 5.95 (2H, s), 6.82 (1H, d, J=2.4Hz), 6.98 (1H, s), 7.01 (1H, dd, J=2.4, 8.8 Hz), 7.76 (1H, d, J=8.8 Hz).

PRODUCTION EXAMPLE 17b 3,4-Dihydroisoquinoline

N-Bromosuccinimide (39.2 g) was added to a methylene chloride solution(300 ml) containing 26.67 g (0.2 mol) of 1,2,3,4-tetrahydroisoquinolineunder ice-cooling over 20 minutes. After stirring for 40 minutes, anaqueous 30% sodium hydroxide solution (130 ml) was added to the reactionsolution. The organic layer was washed with water and then extractedwith a 10% aqueous hydrochloric acid (200 ml). The aqueous layer waswashed with methylene chloride, basified with an aqueous ammonia, andthen extracted with methylene chloride. The extract was dried overmagnesium sulfate and then evaporated. The resulting residue wasdistilled (about 16 mmHg, 120° C.), to give 21.5 g of the title compoundas an oil.

¹H-NMR (DMSO-d₆) δ(ppm): 2.66 (2H, t, J=8 Hz), 3.62 (2H, td, J=2 Hz, 8Hz), 7.19-7.21 (1H, m), 7.29-7.33 (1H, m), 7.35-7.40 (1H, m), 8.31 (1H,t, J=2 Hz).

PRODUCTION EXAMPLE 18b 7-Nitroisoquinoline

15 g of potassium nitrite was added to a concentrated sulfuric acid (70ml) solution containing 18 g (0.14 mol) of 3,4-dihydroisoquinoline wasadded thereto at −15° C. over 20 minutes. After stirring at roomtemperature for one hour, the mixture was heated at 60° C. for 40minutes. The reaction solution was poured into ice-water and basifiedwith an aqueous ammonia. The mixture was extracted with ethyl acetate,and the organic layer was washed with brine and dried over magnesiumsulfate. After concentrating, decaline (100 ml), nitrobenzene (100 ml)and 2 g of Pd-Black were added to the residue, and the mixture washeated at 200° C. overnight in nitrogen stream. The reaction solutionwas washed with ethyl acetate and then extracted with 2N hydrochloricacid. The aqueous layer was washed with ethyl acetate and then anaqueous sodium hydroxide was added thereto. The resulting precipitateswere collected by filtration and washed with water, to give 14.4 g ofthe title compound.

¹H-NMR (CDCl₃) δ(ppm): 7.79 (1H, d, J=5.6 Hz), 8.00 (1H, d, J=9.2 Hz),8.48 (1H, dd, J=2.4 Hz, 9.2 Hz), 8.75 (1H, d, J=5.6 Hz), 8.96 (1H, d,J=2 Hz), 9.48 (1H, s).

PRODUCTION EXAMPLE 19b 4-Bromo-7-nitroisoquinoline

1.2 ml of aqueous HBr and 3 ml of bromine were added to 1.6 g (9.19mmol) of 7-nitroquinoline and the mixture was heated at 180° C. for 5.5hours. The reaction solution was extracted with ethyl acetate. Theextract was successively washed with an aqueous sodium hydroxide, anaqueous sodium thiosulfate and brine, dried over magnesium sulfate andconcentrated. Then, the resulting residue was purified by silica gelcolumn chromatography (eluted with hexane-hexane:ethyl acetate=4:1), togive 500 mg of the title compound.

¹H-NMR (CDCl₃) δ(ppm): 8.36 (1H, d, J=9.2 Hz), 8.58 (1H, d, J=2.4 Hz,9.2 Hz), 8.93 (1H, s), 8.96 (1H, d, J=3.2 Hz), 9.38 (1H, s).

PRODUCTION EXAMPLE 20b 7-Amino-4-bromoisoquinoline

66 mg (0.26 mmol) of 7-nitro-4-bromoisoquinoline was dissolved in 1 mlof ethanol, 2 ml of tetrahydrofuran and 1 ml of water. To the mixturewere added 70 mg of an iron powder and 140 mg of ammonium chloride,followed by heating at 50° C. for 3 hours. A 1N aqueous sodium hydroxidewas added to the reaction solution, and the mixture was extracted withchloroform. The organic layer was dried over magnesium sulfate andconcentrated. The resulting residue was crystallized from isopropylether, to give 33 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 5.98 (2H, s), 6.97 (1H, d, J=2.4 Hz), 7.31 (1H,dd, J=2.4 Hz, 8.8 Hz), 8.28 (1H, s), 8.89 (1H, s).

PRODUCTION EXAMPLE 21b 6-(4-Toluenesulfonylamino)isoquinoline

6-Aminoisoquinoline (3.348 g, Synthesis, 733 (1975)) was dissolved inpyridine (30 ml). To the mixture was added 4-toluenesulfonyl chloride(5.13 g), followed by stirring at room temperature overnight. Water wasadded thereto, and the mixture was extracted with ethyl acetate. Theextract was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was recrystallizedfrom ethanol, to give the title compound (5.958 g, 85%) as pale yellowcrystals.

¹H-NMR (DMSO-d₆) δ(ppm): 2.28 (3H, s), 7.32 (2H, d, J=8.2 Hz), 7.40 (1H,dd, J=1.6, 9.2 Hz), 7.55 (1H, br s), 7.67 (1H, d, J=5.6 Hz), 7.74 (2H,d, J=8.2 Hz), 7.97 (1H, d, J=9.2 Hz), 8.36 (1H, d, J=5.6 Hz), 9.10 (1H,s).

PRODUCTION EXAMPLE 22b 1-Chloro-6-(4-toluenesulfonylamino)isoquinoline

6-(4-Toluenesulfonylamino)isoquinoline (3.0 g, Production Example 21b)was dissolved in chloroform (100 ml). Under ice-cooling,m-chloroperbenzoic acid (2.57 g) was added thereto, followed by stirringat room temperature overnight. The solvent was evaporated, and theresulting crystals were washed with diethyl ether, collected byfiltration and dried, to give pale yellow crystals. The crystals weresuspended in chloroform (83 ml) and phosphorous oxychloride (19 ml) wasadded thereto, followed by heating under reflux for 5 hours. Aftercooling, the solvent was evaporated. The residue was basified by addingan aqueous saturated sodium bicarbonate in an ice bath, and then themixture was extracted with ethyl acetate. The extract was washed withbrine and dried over anhydrous magnesium sulfate, and the solvent wasevaporated. The residue was purified by silica gel column, to give crudecrystals of the title compound (1.630 g, 49.40%). The crystals wererecrystallized from ethanol, to give the title compound as colorlesscrystals.

¹H-NMR (DMSO-d₆) δ(ppm): 2.29 (3H, s), 7.34 (2H, d, J=8.0 Hz), 7.52 (1H,dd, J=2.0, 9.0 Hz), 7.65 (1H, d, J=2.0 Hz), 7.76 (1H, d, J=5.6 Hz), 7.77(2H, d, J=8.0 Hz), 8.14 (1H, d, J=9.0 Hz), 8.16 (1H, d, J=5.6 Hz).

PRODUCTION EXAMPLE 23b 6-Amino-1-chloroisoquinoline

1-Chloro-6-(4-toluenesulfonylamino)isoquinoline (3.323 g, ProductionExample 22b) was dissolved in sulfuric acid (30 ml), followed bystirring at room temperature overnight. The reaction solution was pouredinto ice, and basified by adding an aqueous sodium hydroxide solutionand then potassium carbonate thereto, followed by extracting with ethylacetate. The extract was washed with brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated, to give the titlecompound (1.37 g, 76.81%) as yellowish brown crystals.

¹H-NMR (DMSO-d₆) δ(ppm): 6.23 (2H, br s), 6.76 (1H, s), 7.09 (1H, d,J=9.6 Hz), 7.37 (1H, d, J=6.4 Hz), 7.89 (1H, d, J=9.6 Hz), 7.90 (1H, d,J=6.4 Hz).

PRODUCTION EXAMPLE 24b 2-Chloro-1,6-naphthyridine

1,6-Naphthyridine-2-one (1.0 g, J. Org. Chem. 4744 (1990)) was dissolvedin phosphorous oxychloride (19 ml), followed by heating under reflux at120° C. for 2 hours. After cooling, the solvent was evaporated, and theresidue was basified with water and potassium carbonate. Then, themixture was extracted with ethyl acetate, and the extract was washedwith brine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, to give the title compound (0.658 g, 58.45%) as orangecrystals.

¹H-NMR (CDCl₃) δ(ppm): 7.55 (1H, d, J=8.8 Hz), 7.86 (1H, d, J=6.0 Hz),8.28 (1H, d, J=8.8 Hz), 8.80 (1H, d, J=6.0 Hz), 9.29 (1H, s).

PRODUCTION EXAMPLE 25b 2-Amino-1,6-naphthyridine

2-Chloro-1,6-naphthyridine (0.628 g, Production Example 22b) and anaqueous ammonia (40 ml) were heated at 130° C. for 11 hours in a sealedtube. After cooling, the mixture was extracted with ethyl acetate, andthe extract was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column, to give the title compound (0.497 g, 89.73%) as paleyellow crystals.

¹H-NMR (DMSO-d₆) δ(ppm): 6.81 (1H, d, J=8.8 Hz), 7.24 (1H, d, J=5.8 Hz),7.97 (1H, d, J=8.8 Hz), 8.34 (1H, d, J=5.8 Hz), 8.80 (1H, s).

PRODUCTION EXAMPLE 26b N-(3-Nitrophenethyl)phthalimide

3-Nitrophenethyl alcohol (15 g) was dissolved in tetrahydrofuran (225ml). After adding triphenylphosphine (26 g) and phthalimide (13.9 g)thereto, the mixture was ice-cooled and diethylazodicarboxylate (15.5ml) was added dropwise thereinto. After stirring at room temperature forone hour, the resulting crystals were collected by filtration, washedwith diethyl ether and dried, to give N-(3-nitrophenethyl)phthalimide ascolorless crystals.

¹H-NMR (CDCl₃) δ(ppm): 3.12 (2H, t, J=7.4 Hz), 3.98 (2H, t, J=7.4 Hz),7.47 (1H, dd, J=8.0, 8.0 Hz), 7.60 (1H, d, J=8.0 Hz), 7.72 (2H, m), 7.83(2H, m), 8.09 (1H, d, J=8.0 Hz), 8.12 (1H, s).

PRODUCTION EXAMPLE 27b 3-Nitrophenethylamine

N-(3-Nitrophenethyl)phthalimide obtained in Production Example 26b wassuspended in ethanol (150 ml). To the mixture was added hydrazine (5.7ml), followed by heating under reflux for one hour. The reactionsolution was once dissolved completely, but crystals again precipitated.The crystals were filtered off and washed with cooled ethanol. Then, thesolvent was evaporated, to give the title compound (5.559 g, 99%) as ayellow oil.

¹H-NMR (CDCl₃) δ(ppm): 2.87 (2H, t, J=6.8 Hz), 3.04 (2H, t, J=6.8 Hz),7.48 (1H, dd, J=7.6, 8.4 Hz), 7.55 (1H, ddd, J=1.2, 1.6, 7.6 Hz), 8.08(2H, m).

PRODUCTION EXAMPLE 28b N-Acetyl-N-(3-nitrophenethyl)amine

3-Nitrophenethylamine (5.559 g, Production Example 25b) was dissolved inpyridine (33 ml), and acetyl chloride (2.5 ml) was added dropwisethereinto under ice-cooling. After stirring at room temperature for 0.5hr, the mixture was ice-cooled again. Water was added thereto, and themixture was extracted with ethyl acetate. The extract was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, to give the title compound (6.323 g, 91%) as a yellow oil.

¹H-NMR (CDCl₃) δ(ppm): 1.97 (3H, s), 2.95 (2H, t, J=7.0 Hz), 3.55 (2H,dt, J=6.0, 7.0 Hz), 5.60 (1H, br s), 7.49 (1H, dd, J=7.2, 8.0 Hz), 7.55(1H, d, J=7.2 Hz), 8.07 (1H, s), 8.12 (1H, d, J=8.0 Hz).

PRODUCTION EXAMPLE 29b N-Acetyl-N-(3-aminophenethyl)amine

N-Acetyl-N-(3-nitrophenethyl)amine (2.1 g, Production Example 28b) wasdissolved in ethanol (40 ml). To the mixture were added an iron powder(2.25 g), ammonium acetate (4.3 g) and water (20 ml), followed byheating under reflux for 1.5 hours. Solid was filtered off and washedwith ethanol, and then the filtrate was partially evaporated. Theresidue was extracted with ethyl acetate, washed with brine and driedover anhydrous magnesium sulfate. The solvent was evaporated, to givethe title compound (1.723 g, 96%) as a yellow oil.

¹H-NMR (CDCl₃) δ(ppm): 1.94 (3H, s), 2.72 (2H, t, J=6.8 Hz), 3.50 (2H,dt, J=6.0, 6.8 Hz), 6.53 (1H, s), 6.57 (1H, d, J=8.0 Hz), 6.59 (1H, d,J=7.2 Hz), 7.10 (1H, dd, J=7.2, 8.0 Hz).

PRODUCTION EXAMPLE 30b N-Acetyl-N-(3-ethoxycarbonylaminophenethyl)amine

N-Acetyl-N-(3-aminophenethyl)amine (1.7 g, Production Example 29b) wasdissolved in pyridine (5 ml). Under ice-cooling, ethyl chloroformate(1.4 ml) was added dropwise thereinto, followed by stirring at roomtemperature for one hour. Then, the mixture was ice-cooled again andwater was added thereto. The mixture was extracted with ethyl acetate,and the extract was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, to give the title compound (2.358g, 97%) as a yellow oil.

¹H-NMR (CDCl₃) δ(ppm): 1.29 (3H, t, J=7.2 Hz), 1.93 (3H, s), 2.76 (2H,t, J=7.0 Hz), 3.47 (2H, dt, J=6.0, 7.0 Hz), 4.20 (2H, q, J=7.2 Hz), 5.57(1H, br s), 6.86 (1H, d, J=7.2 Hz), 7.21 (1H, dd, J=7.2, 8.0 Hz), 7.28(1H, d, J=8.0 Hz), 7.29 (1H, s).

PRODUCTION EXAMPLE 31b6-Ethoxycarbonylamino-1-methyl-3,4-dihydroisoquinoline

Using N-acetyl-N-(3-ethoxycarbonylaminophenethyl)amine (1.0 g,Production Example 30b), a cyclization reaction was run according to themethod described in Heterocycles 31 (2), 341 (1990). After the reactionwas completed, the reaction solution was poured into ice and basifiedwith potassium carbonate. Then, the solution was extracted with ethylacetate, and the extract was washed with brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated, to give the titlecompound as a brown oil.

¹H-NMR (CDCl₃) δ(ppm): 1.19 (3H, t, J=7.2 Hz), 2.23 (3H, s), 2.60 (2H,t, J=7.4 Hz), 3.55 (2H, t, J=7.4 Hz), 4.13 (2H, q, J=7.2 Hz), 7.31 (1H,d, J=6.8 Hz), 7.32 (1H, s), 7.34 (1H, d, J=6.8 Hz).

PRODUCTION EXAMPLE 32b 6-Ethoxycarbonylamino-1-methylisoquinoline

p-Cymene (100 ml) and palladium carbon (0.9 g) were added to6-ethoxycarbonylamino-1-methyl-3,4-dihydroisoquinoline, followed byheating under stirring at 195° C. for one hour in a nitrogen atmosphere.The catalyst was filtered off and washed with ethanol, and then thefiltrate was partially evaporated. After extracting with 1N hydrochloricacid, the extract was basified with potassium carbonate and thenextracted with ethyl acetate. The extract was washed with brine anddried over anhydrous magnesium sulfate anhydride. The solvent wasevaporated, to give the title compound (0.629 g, 69%, 2 steps) as paleyellow crystals.

¹H-NMR (CDCl₃) δ(ppm): 1.30 (3H, t, J=7.2 Hz), 2.89 (3H, s), 4.26 (2H,q, J=7.2 Hz), 7.40 (1H, d, J=5.8 Hz), 7.56 (1H, dd, J=1.6, 8.8 Hz), 7.99(1H, d, J=8.8 Hz), 8.05 (1H, d, J=1.6 Hz), 8.30 (1H, d, J=5.6 Hz), 8.37(1H, s).

PRODUCTION EXAMPLE 33b 6-Amino-1-methylisoquinoline

6-Ethoxycarbonylamino-1-methylisoquinoline (0.629 g, Production Example32b) was dissolved in ethanol (20 ml), to which was then added anaqueous 8 N sodium hydroxide solution (6.8 ml), followed by heatingunder reflux for 1.5 hours. After cooling as it was to room temperature,an aqueous saturated ammonium chloride was added thereto and the mixturewas extracted with ethyl acetate. The extract was washed with brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, togive the title compound (0.311 g, 72%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ(ppm): 2.81 (3H, s), 4.24 (2H, br s), 6.60 (1H, d, J=2.0Hz), 6.91 (1H, ddd, J=1.6, 2.0, 8.8 Hz), 7.18 (1H, d, J=5.6 Hz), 7.84(1H, d, J=8.8 Hz), 8.16 (1H, dd, J=1.6, 5.6 Hz).

PRODUCTION EXAMPLE 34b N-t-Butoxycarbonyl-3-nitrophenethylamine

3-Nitrophenethylamine (4.559 g, Production Example 27b) was dissolved intetrahydrofuran (130 ml), to which were then added triethylamine (8.4ml) and di-t-butyl dicarbonate (6.6 g), followed by stirring at roomtemperature for 2 hours. After evaporating the solvent, brine was addedthereto and the mixture was then extracted with ethyl acetate. Theextract was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, to give the title compound (8.789g, including impurities) as a yellow oil. It was used in the nextreaction without being further purified.

¹H-NMR (CDCl₃) δ(ppm): 1.53 (9H, s), 2.92 (2H, t, J=7.6 Hz), 3.42 (2H,dt, J=6.4, 6.8 Hz), 4.58 (1H, br s), 7.48 (1H, dd, J=7.2, 8.0 Hz), 7.54(1H, d, J=8.0 Hz), 8.07 (1H, s), 8.10 (1H, d, J=7.2 Hz).

PRODUCTION EXAMPLE 35b 3-(2-t-Butoxycarbonylaminoethyl)-aniline

The title compound (5.521 g, 76%) was obtained as a yellow oil by usingN-t-butoxycarbonyl-3-nitrophenethylamine (8.789 g, including impurities,Production Example 34b) in the same manner as in Production Example170b.

¹H-NMR (CDCl₃) δ(ppm): 1.44 (9H, s), 2.70 (2H, t, J=7.4 Hz), 3.36 (2H,brq), 4.54 (1H, br s), 6.54 (1H, s), 6.57 (1H, d, J=8.0 Hz), 6.60 (1H,d, J=7.2 Hz), 8.10 (1H, dd, J=7.2, 8.0 Hz).

PRODUCTION EXAMPLE 36b3-(2-Butoxycarbonylaminoethyl)ethoxycarbonylaminobenzene

The title compound (0.320 g) was obtained as a yellow oil by using3-(2-t-butoxycarbonylaminoethyl)aniline (5.521 g, Production Example35b) in the same manner as in Production Example 29b. It was used in thenext reaction without being further purified.

¹H-NMR (CDCl₃) δ(ppm): 1.31 (3H, t, J=7.2 Hz), 1.43 (9H, s), 2.77 (2H,t, J=7.4 Hz), 3.67 (2H, brq), 4.22 (2H, q, J=7.4 Hz), 4.55 (1H, br s),6.52 (1H, br s), 6.89 (1H, m), 7.24 (1H, m).

PRODUCTION EXAMPLE 37b 3-Ethoxycarbonylaminophenethylamine hydrochloride

3-(2-t-Butoxycarbonylaminoethyl)-ethoxycarbonylaminobenzene (14.96 g,Production Example 36b) was dissolved in ethanol (15 ml), to which wasthen added hydrochloric acid (15 ml) under ice-cooling, followed bystirring at room temperature for 20 minutes. Hydrochloric acid (12 ml)and ethanol (15 ml) were added thereto, followed by stirring at roomtemperature for 20 minutes. Then, hydrochloric acid (20 ml) and ethanol(30 ml) were further added thereto, followed by stirring at roomtemperature for 30 minutes. After evaporating (subjecting azeotropicdistillation together with toluene) the solvent, the title compound(11.99 g) was obtained as pale yellow crystals.

¹H-NMR (DMSO-d₆) δ(ppm): 1.22 (3H, t, J=7.2 Hz), 2.82 (2H, m), 2.95 (2H,m), 4.10 (2H, q, J=7.2 Hz), 6.86 (1H, d, J=7.6 Hz), 7.20 (1H, dd, J=7.6,8.4 Hz), 7.31 (1H, d, J=8.4 Hz), 7.36 (1H, s), 8.05 (2H, br s), 9.61(1H, s).

PRODUCTION EXAMPLE 38b 6-Aminoethyl-1,2,3,4-tetrahydroisoquinoline

The title compound (4.226 g, including impurities) was obtained as ayellow oil by using 3-ethoxycarbonylaminophenethylamine hydrochloride(4.7 g) obtained in Production Example 39b according to the methoddescribed in Chem. Pharm. Bull. 42 (8), 1676 (1994).

¹H-NMR (CDCl₃) δ(ppm): 1.29 (3H, t, J=7.2 Hz), 2.68 (1H, br s), 2.83(3H, m), 3.73 (2H, m), 4.20 (2H, q, J=7.2 Hz), 6.77 (1H, s), 6.94 (1H,d, J=8.4 Hz), 7.07 (1H, d, J=8.4 Hz), 7.18 (1H, br s).

PRODUCTION EXAMPLE 39b 6-Ethoxycarbonylaminoisoquinoline

p-Cymene (100 ml) and palladium carbon (0.9 g) were added to6-aminoethyl-1,2,3,4-tetrahydroisoquinoline (10 g, Production Example38b), followed by heating under stirring at 195° C. for one hour in anitrogen atmosphere. The catalyst was filtered off, and the reactionmixture was washed with ethanol. Then, the filtrate was evaporated, andthe resulting crystals were washed with diethyl ether and dried. Thesolvent was evaporated, to give the title compound (6.51 g, 66%) as paleyellow crystals.

¹H-NMR (CDCl₃) δ(ppm): 1.36 (3H, t, J=7.2 Hz), 3.74 (1H, m), 4.29 (2H,q, J=7.2 Hz), 6.70 (1H, d, J=2.0 Hz), 7.46 (1H, dd, J=2.0, 8.8 Hz), 7.58(1H, d, J=6.0 Hz), 7.90 (1H, d, J=8.8 Hz), 8.04 (1H, br s), 8.46 (1H, d,J=6.0 Hz), 9.13 (1H, s).

PRODUCTION EXAMPLE 40b 6-Ethoxycarbonylaminoisoquinoline-N-oxide

The title compound (293 mg) was obtained as pale yellow crystals byusing 6-ethoxycarbonylaminoisoquinoline (250 mg, Production Example 39b)in the same manner as in Production Example 22b.

¹H-NMR (DMSO-d₆) δ(ppm): 1.25 (3H, t, J=7.2 Hz), 4.26 (2H, q, J=7.2 Hz),7.61 (1H, dd, J=2.0, 8.8 Hz), 7 79 (1H, d, J=8.8 Hz), 7.81 (1H, d, J=7.2Hz), 8.04 (1H, dd, J=2.0, 7.2 Hz), 8.79 (1H, s), 8.46 (1H, d, J=6.0 Hz),9.13 (1H, s).

PRODUCTION EXAMPLE 41b 1-Chloro-6-ethoxycarbonylaminoisoquinoline

The title compound (173 mg, 60%, 2 steps) was obtained as pale yellowcrystals by using 6-ethoxycarbonylaminoisoquinoline-N-oxide (250 mg) inthe same manner as in Production Example 22b.

¹H-NMR (CDCl₃) δ(ppm): 1.34 (3H, t, J=7.2 Hz), 4.29 (2H, q, J=7.2 Hz),7.36 (1H, br s), 7.50 (1H, d, J=5.6 Hz), 7.52 (1H, dd, J=2.4, 9.2 Hz),8.11 (1H, m), 8.19 (1H, d, J=5.6 Hz), 8.22 (1H, d, J=9.2 Hz).

PRODUCTION EXAMPLE 42b 1-Methoxy-6-methoxycarbonylaminoisoquinoline

1-Chloro-6-ethoxycarbonylaminoisoquinoline (2.27 g, Production Example41b) was dissolved in dimethyl sulfoxide (45 ml), to which was thenadded a 28% sodium methoxide solution (8.7 ml), followed by heatingunder stirring at 110° C. for 1.5 hours. After cooling as it was to roomtemperature, an aqueous saturated ammonium chloride was added theretoand the mixture was extracted with ethyl acetate. The extract was washedwith brine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, to give the title compound (1.75 g, 84%) as a brown oil.

¹H-NMR (CDCl₃) δ(ppm): 3.74 (3H, s), 4.03 (3H, s), 7.05 (1H, d, J=5.8Hz), 7.41 (1H, dd, J=2.0, 9.2 Hz), 7.86 (1H, d, J=5.8 Hz), 7.90 (1H, brs), 8.06 (1H, d, J=9.2 Hz), 8.08 (1H, br s).

PRODUCTION EXAMPLE 43b 6-Amino-1-methoxyisoquinoline

The title compound (1.04 g, 99%) was obtained as pale brow crystals byusing 1-methoxy-6-methoxycarbonylaminoisoquinoline (1.75 g, ProductionExample 42b) and also methanol as the solvent in the same manner as inProduction Example 41b.

¹H-NMR (CDCl₃) δ(ppm): 4.07 (3H, s), 4.07 (2H, br s), 6.78 (1H, d, J=2.2Hz), 6.88 (1H, dd, J=2.2, 8.8 Hz), 6.95 (1H, d, J=6.0 Hz), 7.84 (1H, d,J=6.0 Hz), 8.03 (1H, d, J=8.8 Hz).

PRODUCTION EXAMPLE 44b N-Propinyl-(3-nitrophenethyl)amine

The title compound (3.070 g, 77%, including impurities) was obtained asa yellow oil by using 3-nitrophenethylamine (3.0 g, Production Example27b) and propionyl chloride (2.5 ml) in the same manner as in ProductionExample 28b.

¹H-NMR (CDCl₃) δ(ppm): 1.14 (3H, t, J=7.6 Hz), 2.19 (2H, q, J=7.6 Hz),2.96 (2H, t, J=6.8 Hz), 3.56 (2H, dt, J=6.4, 6.8 Hz), 7.49 (1H, dd,J=7.6, 8.0 Hz), 7.55 (1H, d, J=7.6 Hz), 8.07 (1H, s), 8.10 (1H, d, J=8.0Hz).

PRODUCTION EXAMPLE 45b N-Propinyl-(3-aminophenethyl)amine

N-Propinyl-(3-nitrophenethyl)amine (3.070 g, Production Example 44b) wasused to run a reaction in the same manner as in Production Example 29b.The resulting residue was purified by silica gel column, to give thetitle compound (0.857 g, 32%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ(ppm): 1.12 (3H, t, J=7.6 Hz), 2.19 (2H, q, J=7.6 Hz),2.71 (2H, t, J=6.8 Hz), 3.49 (2H, dt, J=6.0, 6.8 Hz), 5.56 (1H, br s),6.52 (1H, s), 6.56 (1H, d, J=7.6 Hz), 6.56 (1H, d, J=7.6 Hz), 7.09 (1H,dd, J=7.6, 7.6 Hz).

PRODUCTION EXAMPLE 46b N-Propinyl-(3-ethoxycarbonylaminophenethyl)amine

N-Propinyl-(3-aminophenethyl)amine (0.857 g, Production Example 44b) wasused to run a reaction in the same manner as in Production Example 30b.The resulting residue was purified by silica gel column, to give thetitle compound (0.747 g, 61%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ(ppm): 1.12 (3H, t, J=7.6 Hz), 1.30 (3H, t, J=7.0 Hz),2.16 (2H, q, J=7.6 Hz), 2.78 (2H, t, J=6.8 Hz), 3.50 (2H, dt, J=6.0, 6.8Hz), 4.21 (2H, q, J=7.0 Hz), 6.67 (1H, br s), 6.87 (1H, d, J=6.8 Hz),7.00 (1H, br s), 7.22 (1H, dd, J=6.8, 8.4 Hz), 7.26 (1H, d, J=8.4 Hz),7.28 (1H, s).

PRODUCTION EXAMPLE 47b 6-Ethoxycarbonylamino-1-ethylisoquinoline

6-Ethoxycarbonylamino-1-ethyl-3,4-dihydroisoquinoline was obtained asbrown crystals by using N-propynyl-(3-ethoxycarbonylaminophenethyl)amine(0.747 g, Production Example 46b) in the same manner as in ProductionExamples 31b-32b, and then the title compound (0.516 g, 75%, 2 steps)was obtained as a yellow oil.

The data of the intermediate and the title compound are as follows.6-Ethoxycarbonylamino-1-ethyl-3,4-dihydroisoquinoline

¹H-NMR (CDCl₃) δ(ppm): 1.21 (3H, t, J=7.6 Hz), 1.30 (3H, t, J=7.0 Hz),2.66 (2H, t, J=7.4 Hz), 2.74 (2H, q, J=7.6 Hz), 3.64 (2H, t, J=7.4 Hz),4.23 (2H, q, J=7.0 Hz), 7.32 (1H, d, J=8.4 Hz), 7.37 (1H, s), 7.43 (1H,d, J=8.4 Hz), 7.79 (1H, s). 6-Ethoxycarbonylamino-1-ethylisoquinoline

¹H-NMR (CDCl₃) δ(ppm): 1.32 (3H, t, J=7.0 Hz), 1.41 (3H, t, J=7.6 Hz),3.27 (2H, q, J=7.6 Hz), 4.27 (2H, q, J=7.0 Hz), 7.40 (1H, d, J=6.0 Hz),7.52 (1H, dd, J=2.0, 8.8 Hz), 7.89 (1H, s), 8.02 (1H, d, J=2.0 Hz), 8.25(1H, d, J=8.8 Hz), 8.34 (1H, J=6.0 Hz).

PRODUCTION EXAMPLE 48b 6-Amino-1-ethylisoquinoline

The title compound (0.320 g, 88%) was obtained as pale yellow crystalsby using 6-ethoxycarbonylamino-1-ethylisoquinoline (0.516 g, ProductionExample 47b) in the same manner as in Production Example 33b.

¹H-NMR (CDCl₃) δ(ppm): 1.31 (3H, t, J=7.2 Hz), 3.21 (2H, q, J=7.2 Hz),4.20 (2H, br s), 6.82 (1H, d, J=2.4 Hz), 6.95 (1H, dd, J=2.4, 8.8 Hz),7.21 (1H, d, J=6.0 Hz), 7.94 (1H, d, J=8.8 Hz), 8.24 (1H, d, J=6.0 Hz).

PRODUCTION EXAMPLE 49b 1-Methoxy-4-(3-nitrophenyl)propane-1-ene

Methoxymethylphosphonium chloride (31.1 g) was suspended intetrahydrofuran (200 ml), to which was then added potassium t-butoxide(10.2 g) under ice-cooling. When the reaction solution was changed tored in color, a solution obtained by dissolving 3-nitroacetophenone (10g) in tetrahydrofuran (100 ml) was added thereto little by little byusing a pipette. After stirring at room temperature for 2.5 hours, anaqueous saturated ammonium chloride was added thereto under ice-cooling.The mixture was extracted with ethyl acetate, and the extract was washedwith brine and dried over magnesium sulfate anhydride. The solvent wasevaporated, and the resulting residue was purified by silica gel column,to give the title compound (8.010 g) as a yellow oil.

PRODUCTION EXAMPLE 50b 2-(3-Nitrophenyl)propanal

2 N hydrochloric acid (150 ml) was added to1-methoxy-4-(3-nitrophenyl)propane-1-ene (8.010 g), followed by heatingunder stirring at 80° C. for 4 hours. Then, hydrochloric acid (5 ml) wasadded thereto, followed by heating under reflux for 2.5 hours. Aftercooling, the mixture was neutralized by an aqueous sodium hydroxidesolution and extracted with ethyl acetate. The extract was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, to give the title compound (7.531 g) as a yellow oil.

PRODUCTION EXAMPLE 51b 2-(3-Nitrophenyl)propane-1-ol

2-(3-Nitrophenyl)propanal (7.531 g) was dissolved in ethanol (100 ml),to which was then added sodium borohydride (1.9 g) under ice-cooling,followed by stirring at room temperature for one hour. Brine was addedthereto, followed by extracting with ethyl acetate. The extract waswashed with brine and dried over anhydrous magnesium sulfate. A residueobtained by evaporating the solvent was purified by silica gel column,to give the title compound (6.275 g, 57.19% in 3 steps) as a brown oil.

¹H-NMR (CDCl₃) δ(ppm): 1.34 (3H, d, J=6.8 Hz), 1.51 (1H, br s), 3.09(1H, tq, J=6.8, 6.8 Hz), 3.78 (2H, d, J=6.8 Hz), 7.50 (1H, dd, J=7.6,8.4 Hz), 7.60 (1H, ddd, J=1.2, 1.6, 7.6 Hz), 8.10 (1H, ddd, J=1.2, 2.4,8.4 Hz), 8.13 (1H, dd, J=1.6, 2.4 Hz).

PRODUCTION EXAMPLE 52b 2-(3-Nitrophenyl)propylamine

The title compound was obtained as a yellow oil by using2-(3-nitrophenyl)propane-1-ol (1.908 g, Production Example 51b) in thesame manner as in Production Examples 26b-27b.

PRODUCTION EXAMPLE 53b 1-t-Butoxycarbonylamino-2-(3-nitrophenyl)propane

The reaction was conducted using 2-(3-nitrophenyl)propylamine obtainedin Production Example 52b in the same manner as in Production Example35b. The resulting residue was purified by silica gel column, to givethe title compound (2.626 g) as a yellow oil.

¹H-NMR (CDCl₃) δ(ppm): 1.31 (3H, d, J=6.8 Hz), 1.40 (9H, s), 3.10 (1H,m), 3.26 (1H, m), 3.38 (1H, m), 7.49 (1H, dd, J=7.6, 8.4 Hz), 7.56 (1H,d, J=7.6 Hz), 8.08 (1H, s), 8.10 (1H, d, J=8.4 Hz).

PRODUCTION EXAMPLE 54b 2-(3-Aminophenyl)-1-t-butoxycarbonylaminopropane

The title compound was obtained as a yellow oil by using the obtained1-t-butoxycarbonylamino-2-(3-nitrophenyl)propane (2.626 g) in the samemanner as in Production Examples 29b.

PRODUCTION EXAMPLE 55b1-t-Butoxycarbonylamino-2-(3-ethoxycarbonylaminophenyl)-propane

The reaction was conducted using the obtained2-(3-aminophenyl)-1-t-butoxycarbonylaminopropane in the same manner asin Production Example 30b. The resulting residue was purified by silicagel column, to give the title compound (2.960 g, 77.56% in 3 steps) as abrown oil.

¹H-NMR (CDCl₃) δ(ppm): 1.25 (3H, d, J=7.6 Hz), 1.31 (3H, t, J=7.2 Hz),1.41 (9H, s), 2.90 (1H, m), 3.18 (1H, ddd, J=4.2, 7.6, 9.2 Hz), 3.39(1H, m), 4.42 (2H, q, J=7.6 Hz), 4.45 (1H, br s), δ 87 (1H, br s), 6.94(1H, m), 7.22 (3H, m).

PRODUCTION EXAMPLE 56b6-Ethoxycarbonylamino-4-methyl-1,2,3,4-tetrahydroisoquinoline

The title compound (2.967 g, crude) was obtained as a yellow solid byusing 1-t-butoxycarbonylamino-2-(3-ethoxycarbonylaminophenyl)propane(2.960 g, Production Example 55b) in the same method as in ProductionExamples 38b-39b.

PRODUCTION EXAMPLE 57b 6-Ethoxycarbonylamino-4-methylisoquinoline

The title compound (2.061 g, crude) was obtained as pale yellow crystalsby using the obtained6-ethoxycarbonylamino-4-methyl-1,2,3,4-tetrahydroisoquinoline (2.967 g,crude) in the same manner as in Production Example 40b.

¹H-NMR (CDCl₃) δ(ppm): 1.36 (3H, t, J=7.2 Hz), 2.59 (3H, s), 4.30 (2H,q, J=7.2 Hz), 7.12 (1H, d, J=2.0 Hz), 7.49 (1H, dd, J=2.0, 8.8 Hz), 7.91(1H, d, J=8.8 Hz), 8.12 (1H, s), 8.32 (1H, s), 9.00 (1H, s).

PRODUCTION EXAMPLE 58b 6-Amino-4-methylisoquinoline

The reaction was conducted using the obtained6-ethoxycarbonylamino-4-methylisoquinoline (2.061 g, crude) in the samemanner as in Production Example 30b. The resulting crystals were washedwith diethyl ether and dried, to give the title compound (0.403 g,27.75% in 4 steps) as pale yellow crystals.

¹H-NMR (CDCl₃) δ(ppm): 2.48 (3H, s), 4.18 (2H, br s), 6.95 (1H, d, J=2.0Hz), 7.00 (1H, dd, J=2.0, 8.8 Hz), 7.76 (1H, d, J=8.8 Hz), 8.19 (1H, s),8.86 (1H, s).

PRODUCTION EXAMPLE 59b 2-(3-Nitrophenyl)butane-1-ol

The title compound (5.456 g, 50.08% in 3 steps) was obtained as a yellowoil by using 3-nitropropiophenone (10 g) in the same method as inProduction Examples 52b-55b.

¹H-NMR (CDCl₃) δ(ppm): 0.86 (3H, t, J=7.4 Hz), 1.63 (1H, m), 1.85 (1H,m), 3.24 (1H, m), 3.83 (2H, m), 7.50 (1H, dd, J=7.2, 8.0 Hz), 7.57 (1H,d, J=8.0 Hz), 8.10 (1H, s), 8.13 (1H, d, J=7.2 Hz).

PRODUCTION EXAMPLE 60b 2-(3-Nitrophenyl)butylamine

The title compound (5.247 g) was obtained as a yellow oil by using2-(3-nitrophenyl)butane-1-ol (5.456 g, Production Example 59b) in thesame manner as in Production Examples 26b-27b.

PRODUCTION EXAMPLE 61b 1-t-Butoxycarbonylamino-2-(3-nitrophenyl)butane

Successively, the reaction was conducted using the obtained2-(3-nitrophenyl)butylamine (5.247 g) in the same manner as inProduction Example 27b. The resulting residue was purified by silica gelcolumn, to give the title compound (7.679 g) as a pale yellow oil.

¹H-NMR (CDCl₃) δ(ppm): 0.83 (3H, t, J=7.4 Hz), 1.39 (9H, s), 1.63 (1H,m), 1.79 (1H, m), 2.84 (1H, m), 3.21 (1H, m), 3.52 (1H, m), 4.42 (1H, brs), 7.49 (1H, d, J=7.6 Hz), 7.52 (1H, dd, J=6.8, 7.6 Hz), 8.04 (1H, s),8.10 (1H, d, J=6.8 Hz).

PRODUCTION EXAMPLE 62b 2-(3-Aminophenyl)-1-t-butoxycarbonylaminobutane

The title compound (6.311 g, 85.40% in 4 steps) was obtained as a yellowoil by using 1-t-butoxycarbonylamino-2-(3-nitrophenyl)butane (7.679 g)in the same method as in Production Example 29b.

PRODUCTION EXAMPLE 63b1-t-Butoxycarbonylamino-2-(3-ethoxycarbonylaminophenyl)-butane

The title compound (8.230 g, crude) was obtained as an orange solid byusing the obtained compound in the same method as in Production Example30b.

¹H-NMR (CDCl₃) δ(ppm): 0.81 (3H, t, J=7.4 Hz), 1.31 (3H, t, J=7.2 Hz),1.40 (9H, s), 1.55 (1H, m), 1.68 (1H, m), 2.63 (1H, m), 3.14 (1H, ddd,J=4.8, 8.8, 13.6 Hz), 3.52 (1H, m), 4.22 (2H, q, J=7.2 Hz), 4.38 (1H, brs), δ 63 (1H, br s), 6.87 (1H, m), 7.23 (3H, m).

PRODUCTION EXAMPLE 64b6-Ethoxycarbonylamino-4-ethyl-1,2,3,4-tetrahydroisoquinoline

The title compound was obtained as a brown oil by using1-t-butoxycarbonylamino-2-(3-ethoxycarbonylaminophenyl)butane (8.230 g,crude, Production Example 63b) in the same method as in ProductionExamples 38b-39b.

PRODUCTION EXAMPLE 65b 6-Ethoxycarbonylamino-4-ethylisoquinoline

A reaction was run using the obtained6-ethoxycarbonylamino-4-ethyl-1,2,3,4-tetrahydroisoquinoline (3.0 g) inthe same manner as in Production Example 40b. The resulting crudecrystals were washed with ethanol/diethyl ether and dried, to give thetitle compound as orange crystals.

¹H-NMR (DMSO-d₆) δ(ppm): 1.27 (3H, t, J=7.2 Hz), 1.28 (3H, t, J=7.2 Hz),2.91 (2H, q, J=7.2 Hz), 4.18 (2H, q, J=7.2 Hz), 7.64 (1H, d, J=8.8 Hz),8.00 (1H, d, J=8.8 Hz), 8.25 (1H, s), 8.27 (1H, s), 8.98 (1H, s), 10.12(1H, s).

PRODUCTION EXAMPLE 66b 6-Amino-4-ethylisoquinoline

The reaction was conducted using6-ethoxycarbonylamino-4-ethylisoquinoline in the same manner as inProduction Example 30b. The resulting residue was purified by NH-silicagel column, and the resulting crude crystals were washed with diethylether and dried, to give the title compound (0.637 g) as orangecrystals.

¹H-NMR (CDCl₃) δ(ppm): 1.35 (3H, t, J=7.6 Hz), 2.92 (2H, q, J=7.6 Hz),4.17 (2H, br s), 6.99 (1H, d, J=8.4 Hz), 7.00 (1H, s), 7.77 (1H, d,J=8.4 Hz), 8.21 (1H, s), 8.86 (1H, s).

PRODUCTION EXAMPLE 67b Diethyl methyl-(3-nitrobenzyl)malonate

Sodium (0.7 g) was dissolved in ethanol (45 ml), to which were thenadded diethylmethyl malonate (5.26 ml) and 3-nitrobenzyl chloride (5 g),followed by heating under reflux for 2 hours. The mixture was ice-cooledand an aqueous ammonium chloride was added thereto, followed byextracting with ethyl acetate. The extract was washed with brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, togive the title compound (9.724 g) as a pale yellow oil.

¹H-NMR (CDCl₃) δ(ppm): 1.27 (6H, t, J=7.2 Hz), 1.37 (3H, s), 3.32 (2H,s), 4.21 (4H, q, J=7.2 Hz), 7.44 (1H, d, J=7.6 Hz), 7.48 (1H, dd, J=7.6,7.6 Hz), 8.03 (1H, s), 8.11 (1H, d, J=7.6 Hz).

PRODUCTION EXAMPLE 68b Ethyl 1-methyl-2-(3-nitrophenyl)propionate

The obtained diethyl methyl-(3-nitrobenzyl)malonate (9.724 g) wasdissolved in dimethyl sulfoxide (30 ml), to which were then added water(0.54 ml) and lithium chloride (2.54 g), followed by stirring underheating at 190° C. for 3.5 hours. After cooling as it was, water wasadded thereto, followed by extracting with ethyl acetate. The extractwas washed with brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated, to give the title compound (5.071 g, 73.35% in 2steps) as a brown oil.

¹H-NMR (CDCl₃) δ(ppm): 1.20 (3H, t, J=7.2 Hz), 1.21 (3H, d, J=7.2 Hz),2.79 (2H, m), 3.10 (1H, m), 4.10 (2H, q, J=7.2 Hz), 7.45 (1H, dd, J=7.6,8.0 Hz), 7.52 (1H, d, J=7.6 Hz), 8.06 (1H, s), 8.08 (1H, d, J=8.0 Hz).

PRODUCTION EXAMPLE 69b 1-Methyl-2-(3-nitrophenyl)propionic acid

Ethyl 1-methyl-2-(3-nitrophenyl)propionate (5.071 g, Production Example68b) was dissolved in ethanol (50 ml), to which was then added anaqueous 5 N sodium hydroxide solution (43 ml), followed by heating underreflux for 2.5 hours. After cooling as it was, diethyl ether and waterwere added thereto, and the aqueous layer was separated. The organiclayer was extracted with aqueous saturated sodium bicarbonate. Theaqueous layers were combined, acidified by adding dilute hydrochloricacid, and then extracted with diethyl ether. The extract was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the resulting residue was purified by silica gel column,to give the title compound (2.918 g, 65.27%) as a red oil.

¹H-NMR (CDCl₃) δ(ppm): 1.24 (3H, d, J=6.0 Hz), 2.83 (2H, s), 3.16 (1H,m), 7.47 (1H, dd, J=7.2, 8.0 Hz), 7.54 (1H, d, J=7.2 Hz), 8.08 (1H, s),8.10 (1H, d, J=8.0 Hz).

PRODUCTION EXAMPLE 70b N-Boc-1-methyl-2-(3-nitrophenyl)ethylamine

1-Methyl-2-(3-nitrophenyl)propionic acid (2.918 g, Production Example69b) was dissolved in t-butanol (36 ml), to which were then addedtriethylamine (4.09 ml) and diphenylphosphorylazide, followed by heatingunder reflux for 2.5 hours. After cooling as it was, the solvent wasevaporated. An aqueous saturated sodium bicarbonate was added thereto,followed by extracting with ethyl acetate. The extract was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the resulting residue was purified by silica gel column,to give the title compound (2.117 g, 54.14%) as yellow crystals.

¹H-NMR (CDCl₃) δ(ppm): 1.13 (3H, d, J=6.8 Hz), 2.82 (1H, m), 2.92 (1H,m), 3.94 (1H, br s), 7.47 (1H, dd, J=7.2, 8.0 Hz), 7.54 (1H, d, J=7.2Hz), 8.05 (1H, s), 8.09 (1H, d, J=8.0 Hz).

PRODUCTION EXAMPLE 71b N-Boc-2-(3-aminophenyl)-1-methylethylamine

A reaction was conducted usingN-Boc-1-methyl-2-(3-nitrophenyl)ethylamine (2.117 g, Production Example70b) in the same manner as in Production Example 29b. After extracting,the resulting residue was purified by silica gel column, to give thetitle compound (0.976 g, 51.63%) as a yellow oil.

PRODUCTION EXAMPLE 72bN-Boc-1-methyl-2-(3-ethoxycarbonylaminophenyl)ethylamine

The title compound (1.173 g, crude) was obtained as a yellow oil byusing N-Boc-2-(3-aminophenyl)-1-methylethylamine (0.976 g) in the samemethod as in Production Example 30b. It was used in the next reactionwithout carrying out a further purification.

¹H-NMR (CDCl₃) δ(ppm): 1.09 (3H, d, J=6.4 Hz), 1.31 (3H, t, J=7.2 Hz),1.43 (9H, s), 2.62 (1H, dd, J=6.8 Hz, 13.2 Hz), 2.82 (1H, m), 3.88 (1H,m), 4.22 (2H, q, J=7.2 Hz), 4.38 (1H, m), 6.56 (1H, m), 6.89 (1H, d,J=6.8 Hz), 7.18 (1H, s), 7.22 (1H, dd, J=6.8, 8.0 Hz), 7.23 (1H, d,J=8.0 Hz).

PRODUCTION EXAMPLE 73b2-(3-Ethoxycarbonylaminophenyl)-1-methylethylamine hydrochloride

N-Boc-1-methyl-2-(3-ethoxycarbonylaminophenyl)ethylamine (1.173 g,crude) was dissolved in ethanol (5.0 ml), to which was then addedhydrochloric acid (5 ml), followed by stirring at room temperature for1.5 hours. Then, hydrochloric acid (2.5 ml) was further added thereto,followed by stirring at room temperature for 2 hours. The solvent wasevaporated, to give the title compound (1.148 g, crude) as a yellow oil.It was used in the next reaction without carrying out a furtherpurification.

¹H-NMR (DMSO-d₆) δ(ppm): 1.03 (3H, d, J=6.8 Hz), 1.22 (3H, t, J=7.2 Hz),2.55 (1H, m), 2.95 (1H, m), 3.32 (1H, m), 4.10 (2H, q, J=7.2 Hz), 6.84(1H, d, J=7.2 Hz), 7.21 (1H, dd, J=7.2, 7.2 Hz), 7.29 (1H, d, J=7.2 Hz),7.35 (1H, s), 8.00 (1H, br s), 9.60 (1H, s).

PRODUCTION EXAMPLE 74b6-Ethoxycarbonylamino-3-methyl-1,2,3,4-tetrahydroisoquinoline

The reaction was conducted using2-(3-ethoxycarbonylaminophenyl)-1-methylethylamine hydrochloride (1.148g, Production Example 73b) according to the method of Chem. Pharm. Bull.42 (8), 1676 (1994). The product was purified by NH-silica gel column,to give the title compound (0.441 g).

¹H-NMR (CDCl₃) δ(ppm): 1.24 (3H, d, J=6.4 Hz), 1.30 (3H, t, J=7.2 Hz),2.48 (1H, dd, J=10.0 Hz, 16.4 Hz), 2.75 (1H, dd, J=3.6 Hz, 16.4 Hz),3.01 (1H, m), 4.03 (2H, brq), 4.21 (2H, q, J=7.2 Hz), 6.66 (1H, s), 6.95(1H, d, J=8.4 Hz), 7.09 (1H, d, J=8.4 Hz), 7.14 (1H, s).

PRODUCTION EXAMPLE 75b 6-Ethoxycarbonylamino-3-methylisoquinoline

The title compound (0.356 g) was obtained using the obtained6-ethoxycarbonylamino-3-methyl-1,2,3,4-tetrahydroisoquinoline (0.441 g)in the same method as in Production Example 39b.

¹H-NMR (CDCl₃) δ(ppm): 1.34 (3H, t, J=7.2 Hz), 2.67 (3H, s), 4.28 (2H,q, J=7.2 Hz), 7.08 (1H, br s), 7.39 (1H, dd, J=2.0, 8.8 Hz), 7.40 (1H,s), 7.85 (1H, d, J=8.8 Hz), 7.94 (1H, br s), 9.05 (1H, s).

PRODUCTION EXAMPLE 76b 6-Amino-3-methylisoquinoline

Crude crystals (0.182 g) obtained using the obtained6-ethoxycarbonylamino-3-methylisoquinoline (0.356 g) in the same methodas in Production Example 33b were washed with diethyl ether and dried,to give the title compound (93 g) as pale yellow crystals.

¹H-NMR (CDCl₃) δ(ppm): 2.63 (3H, s), 4.14 (2H, br s), 6.77 (1H, d, J=2.0Hz), 6.93 (1H, dd, J=2.0, 8.8 Hz), 7.18 (1H, s), 7.72 (1H, d, J=8.8 Hz),8.9

SYNTHETIC EXAMPLE 1b N-(8-Bromoquinoline-3-yl)-3-pyridinesulfonamide

3-Amino-8-bromoquinoline (300 mg, Production Example 5b) was dissolvedin pyridine (5 ml), to which was then added 3-pyridinesulfonyl chloride(254 mg), followed by stirring at room temperature for 30 minutes. Afterthe reaction was completed, the reaction solution was poured into brineand extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate and then concentrated. The resulting crude crystalswere washed with ethyl acetate and IPA, to give the title compound (270mg).

¹H-NMR (DMSO-d₆) δ(ppm): 7.47 (1H, t, J=8.0 Hz), 7.52-7.60 (1H, m),7.99-8.03 (2H, m), 8.10 (1H, d, J=2.4 Hz), 8.18-8.22 (1H, m), 8.71 (1H,d, J=2.4 Hz), 8.78 (1H, dd, J=1.6 Hz, 4.8 Hz), 8.98 (1H, d, J=2.4 Hz),11.23 (1H, br s).

SYNTHETIC EXAMPLE 2bN-(5-Bromoquinoline-2-yl)-5-methyl-3-pyridinesulfonamide

The title compound was obtained from 2-amino-5-bromoquinoline(Production Example 1b) and 5-methyl-3-pyridinesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.37 (3H, s), 7.58-7.72 (4H, m), 8.11 (1H, brs), 8.37 (1H, d, J=9.6 Hz), 8.59 (1H, d, J=1.2 Hz), 8.86 (1H, br s).

SYNTHETIC EXAMPLE 3b6-Amino-N-(8-bromoquinoline-3-yl)-3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 5b) and 6-amino-3-pyridinesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 6.40 (1H, d, J=8.8 Hz), 6.93 (2H, br s), 7.44(1H, t, J=8.0 Hz), 7.65 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.96-7.99 (2H, m),8.01 (1H, d, J=2.4 Hz), 8.31 (1H, d, J=2.4 Hz), 8.70 (1H, d, J=2.4 Hz),10.73 (1H, br s).

SYNTHETIC EXAMPLE 4b N-(8-Bromoquinoline-3-yl)-4-cyanobenzenesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 5b) and 4-cyanobenzenesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.46 (1H, t, J=8.0 Hz), 7.96-8.07 (7H, m), 8.70(1H, d, J=2.4 Hz), 11.27 (1H, br s).

SYNTHETIC EXAMPLE 5b6-Chloro-N-(8-bromoquinoline-3-yl)-3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 5b) and 6-chloro-3-pyridinesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.47 (1H, t, J=8.0 Hz), 7.71 (1H, d, J=8.4 Hz),7.99-8.03 (2H, m), 8.10 (1H, d, J=2.4 Hz), 8.20 (1H, dd, J=8.4 Hz), 8.71(1H, d, J=2.4 Hz), 8.83 (1H, d, J=2.4 Hz), 10.73 (1H, br s).

SYNTHETIC EXAMPLE 6bN-(8-Bromoquinoline-3-yl)-4-(N-ethylsulfamoyl)benzenesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 5b) and 4-(N-ethylsulfamoyl)benzenesulfonyl chloridein the same manner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 0.82 (3H, t, J=7.2 Hz), 2.69-2.76 (2H, m), 7.45(1H, t, J=8.4 Hz), 7.75 (1H, t, J=5.6 Hz), 7.90-8.04 (7H, m), 8.70 (1H,d, J=2.8 Hz), 11.18 (1H, br s).

SYNTHETIC EXAMPLE 7bN-(8-Bromoquinoline-3-yl)-5-cyano-2-pyridinesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 5b) and 5-cyano-3-pyridinesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.46 (1H, t, J=8.0 Hz), 7.95 (1H, d, J=8.0 Hz),8.01 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=2.4 Hz), 8.21 (1H, d, J=8.4 Hz),8.57 (1H, dd, J=2.0 Hz, 8.4 Hz), 8.79 (1H, d, J=2.4 Hz), 9.14 (1H, d,J=2.0 Hz), 11.49 (1H, br s).

SYNTHETIC EXAMPLE 8b N-(8-Cyanoquinoline-3-yl)-3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-cyanoquinoline(Production Example 7b) and 3-pyridinesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.59 (1H, dd, J=4.8 Hz, 8.0 Hz), 7.70 (1H, t,J=8.0 Hz), 8.21-8.25 (3H, m), 8.33 (1H, d, J=8.0 Hz), 8.77-8.79 (2H, m),9.01 (1H, d, J=2.8 Hz), 11.34 (1H, br s).

SYNTHETIC EXAMPLE 9b N-(8-Cyanoquinoline-3-yl)-4-cyanobenzenesulfonamide

The title compound was obtained from 3-amino-8-cyanoquinoline(Production Example 7b) and 4-cyanobenzenesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.71 (1H, t, J=8.0 Hz), 7.96-8.07 (4H, m), 8.18(1H, d, J=2.8 Hz), 8.24 (1H, d, J=8.0 Hz), 8.31 (1H, d, J=8.0 Hz), 8.78(1H, d, J=2.8 Hz), 11.37 (1H, br s).

SYNTHETIC EXAMPLE 10b N-(5-Bromoquinoline-2-yl)-3-pyridinesulfonamide

The title compound was obtained from 2-amino-5-bromoquinoline(Production Example 1b) and 3-pyridinesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.57-7.61 (3H, m), 7.70-7.72 (2H, m), 8.28 (1H,br), 8.38 (1H, d, J=9.6 Hz), 8.75 (1H, dd, J=1.2 Hz, 4.8 Hz), 9.07 (1H,br).

SYNTHETIC EXAMPLE 11b N-(8-Bromoquinoline-3-yl)-5-indanesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 5b) and 5-indanesulfonyl chloride in the same manneras in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 1.92-2.01 (2H, m), 2.81-2.86 (4H, m), 7.34 (1H,d, J=8.0 Hz), 7.44 (1H, t, J=8.0 Hz), 7.60 (1H, dd, J=1.6 Hz, 8.0 Hz),7.70 (1H, d, J=1.6 Hz), 7.95 (1H, d, J=8.0 Hz), 7.97 (1H, d, J=8.0 Hz),8.03 (1H, d, J=2.4 Hz), 8.71 (1H, d, J=2.4 Hz), 10.93 (1H, br s).

SYNTHETIC EXAMPLE 12bN-(8-Iodoquinoline-3-yl)-N*-acetyl-5-indolinesulfonamide

The title compound was obtained from 3-amino-8-iodoquinoline (ProductionExample 6b) and N-acetyl-6-indolinesulfonyl chloride in the same manneras in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.11 (3H, s), 3.11 (2H, t, J=8.4 Hz), 4.06 (2H,t, J=8.4 Hz), 7.28 (1H, t, J=8.0 Hz), 7.65-7.68 (2H, m), 7.93-7.96 (2H,m), 8.05 (1H, d, J=9.2 Hz), 8.22 (1H, dd, J=1.2 Hz, 7.6 Hz), 8.64 (1H,d, J=2.4 Hz), 10.87 (1H, br s).

SYNTHETIC EXAMPLE 13b N-(8-Bromoquinoline-3-yl)-3-quinolinesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 5b) and 3-quinolinesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.38 (1H, t, J=8.0 Hz), 7.70-7.74 (1H, m),7.90-8.00 (3H, m), 8.07 (1H, d, J=8.0 Hz), 8.13 (1H, d, J=2.4 Hz), 8.19(1H, dd, J=0.8 Hz, 8.4 Hz), 8.75 (1H, d, J=2.4 Hz), 9.00-9.01 (1H, m),9.19 (1H, d, J=2.4 Hz), 11.31 (1H, br s).

SYNTHETIC EXAMPLE 14bN-(8-Bromoquinoline-3-yl)-N*-acetyl-1,2,3,4-tetrahydroquinoline-6-sulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 5b) andN-acetyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 1.86-2.01 (2H, m), 2.77 (2H, t, J=6.4 Hz),3.65-3.76 (2H, m),

SYNTHETIC EXAMPLE 15b N-(8-Iodoquinoline-3-yl)-4-isoquinolinesulfonamide

The title compound was obtained from 3-amino-8-iodoquinoline (ProductionExample 6b) and 4-isoquinolinesulfonyl chloride in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.26 (1H, t, J=8.0 Hz), 7.82-7.86 (1H, m),7.93-7.95 (1H, m), 7.98 (1H, d, J=2.4 Hz), 8.02-8.06 (1H, m), 8.19 (1H,dd, J=1.2 Hz, 7.6 Hz), 8.27 (1H, d, J=8.4 Hz), 8.59 (1H, d, J=2.4 Hz),8.67 (1H, d, J=8.4 Hz), 9.12 (1H, s), 9.52 (1H, s), 11.57 (1H, br s).

SYNTHETIC EXAMPLE 16b4-Cyano-N-(8-iodoquinoline-3-yl)-benzenesulfonamide

The title compound was obtained from 3-amino-8-iodoquinoline (ProductionExample 6b) and 4-cyanobenzenesulfonyl chloride in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.31 (1H, t, J=8.0 Hz), 7.96-8.04 (6H, m), 8.26(1H, dd, J=1.2 Hz, 7.2 Hz), 8.65 (1H, d, J=2.8 Hz), 11.24 (1H, br s).

SYNTHETIC EXAMPLE 17b N-(8-Iodoquinoline-3-yl)-3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-iodoquinoline (ProductionExample 6b) and 3-pyridinesulfonyl chloride in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.31 (1H, t, J=8.0 Hz), 7.57-7.60 (1H, m), 7.99(1H, d, J=1.2 Hz, 8.4 Hz), 8.04 (1H, d, J=2.8 Hz), 8.18-8.21 (1H, m),8.26 (1H, dd, 1.2 Hz, 7.2 Hz), 8.66 (1H, d, J=2.8 Hz), 8.77 (1H, dd,J=1.6 Hz, 4.8 Hz), 8.98 (1H, d, J=2.8 Hz), 11.20 (1H, br s).

SYNTHETIC EXAMPLE 18bN-(5-Bromoquinoline-2-yl)-4-cyanobenzenesulfonamide

The title compound was obtained from 2-amino-5-bromoquinoline(Production Example 1b) and 4-cyanobenzenesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.57-7.73 (4H, m), 8.00-8.08 (4H, m), 8.38 (1H,d, J=8.8 Hz).

SYNTHETIC EXAMPLE 19bN-(8-Bromoquinoline-3-yl)-6-ethyl-3-pyridinesulfonamide

Pyridine (0.5 ml) and a methylene chloride (0.5 ml) solution containing6-ethyl-3-pyridinesulfonyl chloride (30 ml) were added to3-amino-8-bromoquinoline (18 mg, Production Example 5b) at 0° C. Afterstirring at room temperature for 30 minutes, water was added thereto andthe mixture was extracted with ethyl acetate. The extract was purifiedby preparative TLC (hexane-ethyl acetate=1:1), to give the titlecompound (20 mg).

¹H-NMR (CDCl₃) δ(ppm): 1.25 (3H, t, J=7.5 Hz), 2.70 (2H, q, J=7.50 Hz),7.34-7.98 (5H, m), 8.19 (1H, d, J=3.3 Hz), 8.54 (1H, s), 8.83 (1H, d,J=3.3 Hz).

SYNTHETIC EXAMPLE 20b4-Chloro-N-(5-chloroquinoline-2-yl)-benzenesulfonamide

Pyridine (1 ml) and 4-chlorobenzenesulfonyl chloride (255 mg) were addedto 2-amino-5-chloroquinoline (119 mg, Production Example 2b) at roomtemperature, followed by stirring at room temperature for 3 days. Then,water was added thereto, followed by extracting with ethyl acetate. Theethyl acetate layer was dried over sodium sulfate and concentrated.Then, the resulting solid was washed with methanol, to give the titlecompound (20 mg).

¹H-NMR (CDCl₃) δ(ppm): 6.96 (1H, d, J=9.7 Hz), 7.34 (1H, d, J=8.4 Hz),7.42-7.48 (3H, m), 7.54 (1H, t, J=8.4 Hz), 7.94 (2H, d, J=6.3 Hz), 8.29(1H, d, J=9.7 Hz).

SYNTHETIC EXAMPLE 21bN-(8-Chloroquinoline-3-yl)-6-ethyl-3-pyridinesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Production Example 9b) and 6-ethyl-3-pyridinesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 1.28 (3H, t, J=8.3 Hz), 2.86 (2H, q, J=8.3 Hz),7.24 (1H, d, J=8.0 Hz), 7.49 (1H, t, J=8.0 Hz), 7.73 (1H, d, J=8.0 Hz),7.78 (1H, d, J=8.0 Hz), 7.95 (1H, dd, J=8.0 Hz, 2.1 Hz), 8.18 (1H, d,J=2.5 Hz), 8.67 (1H, d, J=2.5 Hz), 8.93 (1H, d, J=2.1 Hz).

SYNTHETIC EXAMPLE 22bN-(5-Chloroquinoline-2-yl)-6-ethyl-3-pyridinesulfonamide

The title compound was obtained from 2-amino-5-chloroquinoline(Production Example 2b) and 6-ethyl-3-pyridinesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 1.32 (3H, t, J=8.3 Hz), 2.89 (2H, q, J=8.3 Hz),6.97 (1H, d, J=9.4 Hz), 7.29 (1H, d, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz),7.44 (1H, d, J=8.0 Hz), 7.56 (1H, t, J=8.0 Hz), 8.18 (1H, dd, J=8.0 Hz,2.6 Hz), 8.30 (1H, d, J=9.4 Hz), 9.10 (1H, d, J=2.6 Hz).

SYNTHETIC EXAMPLE 23b N-(8-Chloroquinoline-3-yl)-benzenesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Production Example 9b) and benzenesulfonyl chloride in the same manneras in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.30-7.48 (6H, m), 7.84 (2H, d, J=7.4 Hz), 8.11(1H, d, J=3.1 Hz), 8.66 (1H, d, J=3.1 Hz).

SYNTHETIC EXAMPLE 24b4-Cyano-N-(5-chloroquinoline-2-yl)-benzenesulfonamide

The title compound was obtained from 3-amino-8-bromoquinoline(Production Example 2b) and 4-cyanobenzenesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 6.96 (1H, d, J=9.5 Hz), 7.35 (1H, d, J=8.7 Hz),7.45 (1H, d, J=8.7 Hz), 7.57 (1H, t J=8.7 Hz), 7.78 (2H, d, J=8.9 Hz),8.10 (2H, d, J=8.9 Hz), 8.33 (1H, d, J=9.5 Hz).

SYNTHETIC EXAMPLE 25bN-(5-Chloroquinoline-2-yl)-4-methylbenzenesulfonamide

The title compound was obtained from 2-amino-5-chloroquinoline(Production Example 2b) and 4-toluenesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 2.41 (3H, s), 6.98 (1H, d, J=9.3 Hz), 7.28 (2H,d, J=8.2 Hz), 7.35 (1H, d, J=7.9 Hz), 7.41 (1H, d, J=7.9 Hz), 7.53 (1H,t, J=7.9 Hz), 7.88 (2H, d, J=8.2 Hz), 8.26 (1H, d, J=9.3 Hz).

SYNTHETIC EXAMPLE 26bN-(5-Chloroquinoline-2-yl)-4-sulfamoylbenzenesulfonamide

The title compound was obtained from 2-amino-5-chloroquinoline(Production Example 2b) and 4-sulfamoylbenzenesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 7.42-7.49 (3H, m,), 7.58 (1H, t, J=8.0 Hz),8.00-8.12 (4H, m,) 8.39 (1H, d, J=9.3 Hz).

SYNTHETIC EXAMPLE 27bN-(5-Bromoquinoline-2-yl)-4-(N-ethylsulfamoyl)benzenesulfonamide

The title compound was obtained from 2-amino-5-chloroquinoline(Production Example 2b) and 4-(N-ethylsulfamoyl)benzenesulfonyl chloridein the same manner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 1.14 (3H, t, J=7.5 Hz), 3.01-3.09 (2H, m), 7.08(1H, d, J=9.5 Hz), 7.42 (1H, dd, J=7.6 Hz, 1.3 Hz), 7.49 (1H, t, J=7.6Hz), 7.65 (1H, dd, J=7.6 Hz, 1.3 Hz), 7.96 (2H, d, J=8.7 Hz), 8.10 (2H,d, J=8.7 Hz), 8.31 (1H, d, J=9.5 Hz).

SYNTHETIC EXAMPLE 28b3-Cyano-N-(8-chloroquinoline-3-yl)benzenesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Production Example 9b) and 3-cyanobenzenesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 7.52 (1H, t, J=7.9 Hz), 7.59 (1H, t, J=7.9 Hz),7.72-7.86 (3H, m), 8.00 (1H, d, J=7.9 Hz), 8.13 (1H, d, J=3.2 Hz), 8.16(1H, s), 8.64 (1H, d, J=3.2 Hz).

SYNTHETIC EXAMPLE 29bN-(8-Chloroquinoline-3-yl)-3-methylbenzenesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Production Example 9b) and 3-toluenesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 2.35 (3H, s), 7.16-7.79 (7H, m), 8.09 (1H, d,J=2.7 Hz), 8.65 (1H, d, J=2.7 Hz).

SYNTHETIC EXAMPLE 30bN-(8-Chloroquinoline-3-yl)-3-sulfamoylbenzenesulfonamide

The title compound was obtained from 3-amino-8-chloroquinoline(Production Example 9b) and 3-sulfamoylbenzenesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 7.46 (1H, t, J=7.6 Hz), 7.53 (1H, t, J=7.6 Hz),7.58-7.78 (2H, m), 8.00 (1H, d, J=7.6 Hz), 8.04 (1H, d, J=7.6 Hz), 8.14(1H, d, J=2.8 Hz), 8.47 (1H, s), 8.59 (1H, d, J=2.8 Hz).

SYNTHETIC EXAMPLE 31b N-(8-Methylquinoline-3-yl)-3-pyridinesulfonamide

562 mg of white crystals were obtained using 1.02 g (5.2 mmol,Production Example 16b) of 7-amino-2-chloro-4-methylquinoline and 0.9 g(5.2 mmol) of 3-pyridinesulfonyl chloride in the same manner as inSynthetic Example 1b. Methanol (4 ml), tetrahydrofuran (4 ml) and 10%palladium carbon (5 mg) were added to 102 mg (0.29 mmol) of the whitecrystals, followed by stirring for 6 hours in a hydrogen atmosphere. Thereaction solution was filtered through Celite, and then evaporated. Theresidue was washed with ethyl acetate, to give 65 mg of the titlecompound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.82 (3H, s), 7.64-7.66 (2H, m), 7.73 (1H, d,J=5.2 Hz), 8.03 (1H, s), 8.30-8.35 (2H, m), 8.82 (1H, dd, J=1.2, 4.8Hz), 9.00 (1H, d, J=5.2 Hz), 9.11 (1H, d, J=2.0 Hz).

SYNTHETIC EXAMPLE 32bN-(8-Methylquinoline-3-yl)-4-cyanobenzenesulfonamide

358 mg of white crystals were obtained using 305 mg (1.58 mmol,Production Example 16b) of 7-amino-2-chloro-4-methylquinoline and 0.48 g(2.4 mmol) of 4-cyanobenzenesulfonyl chloride in the same manner as inSynthetic Example 1b. Acetic acid (6 ml), water (2 ml) and zinc (122 mg)were added to 140 mg (0.38 mmol) of the white crystals, followed bystirring at 60° C. for 15 minutes. After the reaction solution wasfiltered through Celite, an aqueous saturated sodium bicarbonatesolution was added, followed by extracting with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated. Then, the residue was purified by silica gelchromatography, to give 82 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.60 (3H, s), 7.26 (1H, dd, J=1.2, 4.4 Hz),7.41 (1H, dd, J=2.4, 8.8 Hz), 7.64 (1H, d, J=2.4 Hz), 7.97-8.06 (1H, m),7.98 (2H, d, J=8.4 Hz), 8.04 (2H, d, J=8.4 Hz), 8.66 (1H, d, J=4.4 Hz),11.06 (1H, s).

SYNTHETIC EXAMPLE 33bN-(6-Chloro-8-cyanoquinoline-3-yl)-3-pyridinesulfonamide

764 mg of white crystals were obtained using 3.0 mg (13 mmol, ProductionExample 13b) of ethyl-7-amino-2-chloroquinoline-4-carboxylate and 2.3 g(13 mmol) of 3-pyridinesulfonyl chloride in the same manner as inSynthetic Example 1b. An aqueous 1 N sodium hydroxide solution (0.5 ml)was added to an ethanol solution (6 ml) of 108 mg (0.28 mmol) of thewhite crystals, followed by stirring overnight. An aqueous 1 Nhydrochloric acid solution was added to the reaction solution, followedby extracting with ethyl acetate twice. The organic layer was washedwith brine, dried over magnesium sulfate and concentrated, to give theresidue. Under ice-cooling, oxalyl chloride (0.04 ml) and one droplet ofdimethylformamide were added to a tetrahydrofuran solution (10 ml)containing the residue, followed by stirring at room temperature for 30minutes. After 30 minutes, an aqueous saturated ammonium solution (5 ml)was added thereto, followed by stirring for further 10 minutes. Brinewas added to the reaction solution, followed by extracting with ethylacetate. The organic layer was dried over magnesium sulfate andconcentrated, to give the residue. Under ice-cooling, pyridine (0.06 ml)and trifluoroacetic acid anhydride (0.05 ml) were added to atetrahydrofuran solution (6 ml) containing the residue, followed bystirring at room temperature for 30 minutes. Brine was added to thereaction solution, followed by extracting with ethyl acetate. Theorganic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by silica gel chromatography, to give 37 mg of thetitle compound.

¹H-NMR (DMSO-d₆) δ(ppm): 7.62-7.66 (1H, m), 7.68-7.72 (2H, m), 8.08 (1H,d, J=8.8 Hz), 8.23 (1H, s), 8.26-8.29 (1H, m), 8.81 (1H, dd, J=1.6, 4.8Hz), 9.04 (1H, d, J=2.4 Hz).

SYNTHETIC EXAMPLE 34bN-(8-Chloroquinoline-3-yl)-4-cyanobenzenesulfonamide

58 mg of the title compound was obtained using 38 mg (0.21 mmol) of3-amino-8-chloroquinoline (0.21 mmol, Production Example 9b) and 43 mg(0.21 mmol) of 4-cyanobenzenesulfonyl chloride in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.55 (1H, t, J=7.6 Hz), 7.84 (1H, d, J=7.6 Hz),7.95 (1H, t, J=7.6 Hz), 7.99 (2H, d, J=8.8 Hz), 8.04 (2H, d, J=8.8 Hz),8.09 (1H, d, J=2.8 Hz), 8.73 (1H, d, J=2.8 Hz), 11.39 (1H, s).

SYNTHETIC EXAMPLE 35bN-(8-Chloroquinoline-3-yl)-4-(N-ethylsulfamoyl)benzenesulfonamide

36 mg of the title compound was obtained using 36 mg (0.19 mmol,Production Example 9b) of 3-amino-8-chloroquinoline and 52 mg (0.19mmol) of 4-(N-ethylsulfamoyl)benzenesulfonyl chloride in the same manneras in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 0.84 (3H, t, J=7.2 Hz), 2.78-2.71 (2H, m), 7.54(1H, t, J=7.6 Hz), 7.77 (1H, t, J=6.0 Hz), 7.83 (1H, t, J=7.6 Hz),7.92-7.95 (1H, m), 7.93 (2H, d, J=8.8 Hz), 8.03 (2H, d, J=8.8 Hz), 8.07(1H, d, J=2.4 Hz), 8.73 (1H, d, J=2.4 Hz), 11.20 (1H, s).

SYNTHETIC EXAMPLE 36b N-(8-Chloroquinoline-3-yl)-3-pyridinesulfonamide

29 mg of the title compound was obtained using 33 mg (0.19 mmol,Production Example 9b) of 3-amino-8-chloroquinoline and 33 mg (0.19mmol) of 3-pyridinesulfonyl chloride in the same manner as in SyntheticExample 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.54 (1H, t, J=7.6 Hz), 7.60 (1H, dd, J=4.8,7.6 Hz), 7.81 (1H, d, J=7.6 Hz), 7.94 (1H, d, J=7.6 Hz), 8.09 (1H, d,J=2.8 Hz), 8.19-8.26 (1H, m), 8.72 (1H, d, J=2.8 Hz), 8.77 (1H, d,J=1.6, 4.8 Hz), 9.00 (1H, d, J=2.8 Hz), 11.46 (1H, s).

SYNTHETIC EXAMPLE 37bN-(8-Chloroquinoline-3-yl)-5-ethylsulfamoyl-2-pyridinesulfonamide

10 mg of the title compound was obtained using 30 mg (0.17 mmol,Production Example 9b) of 3-amino-8-chloroquinoline and 95 mg (0.34mmol) of 5-ethylsulfamoyl-2-chlorosulfonylpyridine in the same manner asin Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 0.88 (3H, t, J=7.6 Hz), 2.79-2.86 (2H, m), 7.55(1H, t, J=7.6 Hz), 7.85 (1H, t, J=7.6 Hz), 7.94 (1H, d, J=7.6 Hz), 8.00(1H, t, J=6.4 Hz), 8.16 (1H, d, J=2.8 Hz), 8.27 (1H, d, J=8.0 Hz), 8.41(1H, d, J=2.4, 8.0 Hz), 8.84 (1H, d, J=2.8 Hz), 9.04 (1H, d, J=2.4 Hz),11.47 (1H, s).

SYNTHETIC EXAMPLE 38bN-(8-Trifluoromethylquinoline-3-yl)-4-cyanobenzenesulfonamide

59 mg of the title compound was obtained using 35 mg (0.17 mmol,Production Example 10b) of 3-amino-8-trifluoromethylquinoline and 37 mg(0.18 mmol) of 4-cyanobenzenesulfonyl chloride in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.71 (1H, t, J=7.6 Hz), 8.03-8.09 (5H, m), 8.19(1H, d, J=2.4 Hz), 8.30 (1H, d, J=7.6 Hz), 8.78 (1H, d, J=2.4 Hz), 11.72(1H, s).

SYNTHETIC EXAMPLE 39bN-(8-Trifluoromethylquinoline-3-yl)-4-(N-ethylsulfamoyl)benzenesulfonamide

60 mg of the title compound was obtained using 35 mg (0.17 mmol,Production Example 10b) of 3-amino-8-trifluoromethylquinoline and 56 mg(0.20 mmol) of 4-(N-ethylsulfamoyl)benzenesulfonyl chloride in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 0.83 (3H, t, J=7.2 Hz), 2.71-2.78 (2H, m), 7.69(1H, t, J=8.0 Hz), 7.76 (1H, t, J=5.6 Hz), 7.93 (1H, d, J=8.8 Hz),8.04-8.07 (3H, m), 8.13 (1H, d, J=2.8 Hz), 8.25 (1H, d, J=8.0 Hz), 8.75(1H, d, J=2.8 Hz), 11.28 (1H, s).

SYNTHETIC EXAMPLE 40bN-(8-Trifluoromethylquinoline-3-yl)-3-pyridinesulfonamide

71 mg of the title compound was obtained using 45 mg (0.21 mmol,Production Example 10b) of 3-amino-8-trifluoromethylquinoline and 45 mg(0.25 mmol) of 3-pyridinesulfonyl chloride in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.59-7.63 (1H, m), 7.70 (1H, t, J=7.6 Hz), 8.06(1H, d, J=7.6 Hz), 8.20 (1H, d, J=2.8 Hz), 8.23-8.24 (1H, m), 8.30 (1H,d, J=7.6 Hz), 8.76 (1H, d, J=2.8 Hz), 8.79 (1H, dd, J=1.6, 4.8 Hz), 9.03(1H, d, J=2.0 Hz), 11.64 (1H, s).

SYNTHETIC EXAMPLE 41bN-(8-Chloroquinoline-3-yl)-1,2,3,4-tetrahydro-6-naphthalenesulfonamide

46 mg of the title compound was obtained using 33 mg (0.19 mmol,Production Example 9b) of 3-amino-8-chloroquinoline and 73 mg (0.22mmol) of 6-chlorosulfonyl-1,2,3,4-tetrahydronaphthalene in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 1.68 (4H, br), 2.71 (4H, br), 7.20 (1H, t,J=8.4 Hz), 7.52 (1H, t, J=7.6 Hz), 7.53 (1H, dd, J=2.0, 8.4 Hz), 7.58(1H, d, J=2.0 Hz), 7.80 (1H, d, J=7.6 Hz), 7.93 (1H, d, J=7.6 Hz), 8.06(1H, d, J=2.4 Hz), 8.73 (1H, d, J=2.4 Hz), 10.94 (1H, s).

SYNTHETIC EXAMPLE 42bN-(8-Chloroquinoline-3-yl)-2,3-dihydro-5-benzofuransulfonamide

57 mg of the title compound was obtained using 30 mg (0.17 mmol,Production Example 9b) of 3-amino-8-chloroquinoline and 44 mg (0.20mmol) of 5-chlorosulfonyl-2,3-dihydrobenzofuran in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 3.19 (2H, t, J=8.8 Hz), 4.58 (2H, t, J=8.8 Hz),6.86 (1H, d, J=8.8 Hz), 7.23 (1H, t, J=7.6 Hz), 7.62 (1H, dd, J=1.6, 8.8Hz), 7.72 (1H, d, J=1.6 Hz), 7.80 (1H, d, J=7.6 Hz), 7.92 (1H, d, J=7.6Hz), 8.03 (1H, d, J=2.4 Hz), 8.73 (1H, d, J=2.4 Hz), 10.85 (1H, s).

SYNTHETIC EXAMPLE 43bN-(8-Chloro-4-vinylquinoline-3-yl)-4-cyanobenzenesulfonamide

15 mg of the title compound was obtained using 30 mg (0.15 mmol,Production Example 12b) of 3-amino-4-vinyl-8-chloroquinoline and 36 mg(0.18 mmol) of 4-cyanobenzenesulfonyl chloride in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 5.29 (1H, d, J=17.6 Hz), 5.59 (1H, d, J=11.6Hz), 6.75 (1H, dd, J=11.6, 17.6 Hz), 7.59 (1H, t, J=8.0 Hz), 7.80 (2H,dd, J=8.8 Hz), 7.96 (1H, d, J=8.0 Hz), 8.00-8.04 (3H, m), 8.74 (1H, s),10.58 (1H, s).

SYNTHETIC EXAMPLE 44bN-(8-Trifluoromethylquinoline-3-yl)-5-(N-acethylindoline)sulfonamide

186 mg of the title compound was obtained using 109 mg (0.51 mmol,Production Example 10b) of 3-amino-8-trifluoromethylquinoline and 200 mg(0.77 mmol) of 5-chlorosulfonyl-N-acethylindoline in the same manner asin Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.13 (3H, s), 3.14 (2H, t, J=8.0 Hz), 4.09 (2H,t, J=8.8 Hz), 7.67 (1H, t, J=8.4 Hz), 7.69-7.73 (2H, m), 8.01 (1H, d,J=7.2 Hz), 8.07-8.09 (2H, m), 8.24 (1H, d, J=8.4 Hz), 8.73 (1H, d, J=2.8Hz), 10.98 (1H, s).

SYNTHETIC EXAMPLE 45bN-(8-Bromoquinoline-3-yl)-2-methylthio-5-pyridinesulfonamide

197 mg (0.556 mmol) of white crystals were obtained using 100 mg (0.56mmol, Production Example 5b) of 3-amino-8-bromoquinoline and 142 mg(0.67 mmol) of 2-chloro-5-pyridinesulfonyl chloride in the same manneras in Synthetic Example 1b. Dimethylformamide (1 ml), pyridine (1 ml)and 111 mg (1.6 mmol) of sodium thiomethoxide were added to 60 mg (0.17mmol) of the crystals, followed by stirring at room temperature for 3hours. Brine was added to the reaction solution, followed by extractingwith ethyl acetate. The organic layer was dried over magnesium sulfateand concentrated, to give the residue. The residue was purified bysilica gel chromatography, to give 62 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 3.33 (3H, s), 7.47 (1H, d, J=8.8 Hz), 7.55 (1H,t, J=8.0 Hz), 7.84 (1H, d, J=6.8 Hz), 7.97 (1H, d, J=8.8 Hz), 7.98 (1H,d, J=8.8 Hz), 8.13 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=2.4 Hz), 8.82 (1H,d, J=2.0 Hz), 11.16 (1H, s).

SYNTHETIC EXAMPLE 46bN-(8-Bromoquinoline-3-yl)-4-(2-methylsulfonylethyl)benzenesulfonamide

55 mg of the title compound was obtained using 30 mg (0.13 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 57 mg (0.20 mmol)of 4-(2-methylsulfonylethyl)benzenesulfonyl chloride in the same manneras in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.92 (3H, s), 3.00-3.05 (2H, m), 3.37-3.44 (2H,m), 7.46 (1H, t, J=7.6 Hz), 7.48 (2H, d, J=8.0 Hz), 7.80 (2H, d, J=8.0Hz), 7.96 (1H, d, J=7.6 Hz), 7.99 (1H, d, J=7.6 Hz), 8.04 (1H, d, J=2.4Hz), 8.71 (1H, d, J=2.4 Hz), 11.02 (1H, s)

SYNTHETIC EXAMPLE 47bN-(8-Bromoquinoline-3-yl)-4-oxa-7-benzothiochromansulfonamide

99 mg of the title compound was obtained using 51 mg (0.23 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 86 mg (0.34 mmol)of 7-chlorosulfonyl-4-oxa-benzothiochroman in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 3.18 (2H, t, J=8.4 Hz), 4.39 (2H, t, J=8.4 Hz),6.92 (1H, d, J=8.8 Hz), 7.42 (1H, dd, J=2.4, 8.8 Hz), 7.46 (1H, t, J=7.6Hz), 7.59 (1H, d, J=2.4 Hz), 7.99 (1H, d, J=7.6 Hz), 8.02 (1H, d, J=7.6Hz), 8.05 (1H, br), 8.71 (1H, d, J=2.4 Hz), 10.92 (1H, s).

SYNTHETIC EXAMPLE 48bN-(8-Bromoquinoline-3-yl)-4-(2-acetamidoethyl)benzenesulfonamide

56 mg of the title compound was obtained using 30 mg (0.13 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 201 mg (0.77mmol) of N-(4-chlorosulfonylphenethylethyl)acetamide in the same manneras in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.71 (2H, t, J=7.2 Hz), 3.25-3.20 (2H, m), 7.37(2H, d, J=8.4 Hz), 7.46 (1H, t, J=8.0 Hz), 7.78 (2H, d, J=8.4 Hz), 7.86(1H, br), 7.97 (1H, d, J=8.0 Hz), 8.00 (1H, d, J=8.0 Hz), 8.04 (1H, d,J=2.8 Hz), 8.72 (1H, d, J=2.8 Hz), 10.99 (1H, s).

SYNTHETIC EXAMPLE 49bN-(8-Bromoquinoline-3-yl)-1,2,3,4-tetrahydro-N-acetyl-7-isoquinolinesulfonamide

180 mg of white crystals were obtained using 145 mg (0.65 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 277 mg (0.85mmol) of 1,2,3,4-tetrahydro-2-(trifluoroacetyl)isoquinoline-7-sulfonylchloride in the same manner as in Synthetic Example 1b. Ethanol (20 ml)and an aqueous 1 N sodium hydroxide solution (0.5 ml) were added to thecrystals, followed by stirring at room temperature for 30 minutes. Anaqueous 1 N hydrochloric acid solution (0.4 ml) was added to thereaction solution, followed by extracting with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated, to give the residue. Pyridine (0.5 ml) and acetic acidanhydride (0.014 ml) were added to the residue, followed by stirring atroom temperature for one hour. Brine was added thereto, followed byextracting with ethyl acetate. The organic layer was dried overmagnesium sulfate and concentrated. Then, the residue was purified bysilica gel chromatography, to give 113 mg of the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 1.19-1.28 (2H, m), 2.05 (3H, s), 2.97 (1H, t,J=6.4 Hz), 3.03 (1H, t, J=6.4 Hz), 3.75 (1H, t, J=6.4 Hz), 4.73 (1H, s),7.37 (1H, t, J=8.8 Hz), 7.53-7.58 (1H, m), 7.75-7.87 (2H, m), 7.91 (1H,d, J=8.0 Hz), 8.19-8.27 (2H, m), 8.76-8.78 (1H, m).

SYNTHETIC EXAMPLE 50bN-(8-Bromoquinoline-3-yl)-1,1-dioxido-6-benzothiochromansulfonamide

White crystals were obtained using 71 mg (0.32 mmol, Production Example5b) of 3-amino-8-bromoquinoline and 119 mg (0.48 mmol) of6-chlorosulfonylbenzothiochroman. Under ice-cooling, chloroform (10 ml)and methachloroperbenzoic acid (145 mg) were added to the crystals underice-cooling, followed by stirring at room temperature for one hour. Anaqueous saturated sodium thiosulfate solution was added thereto,followed by extracting with ethyl acetate. The organic layer was washedwith brine and dried over magnesium sulfate. After concentrating, theresidue was purified by silica gel chromatography, to give 113 mg of thetitle compound.

¹H-NMR (DMSO-d₆) δ(ppm): 2.26-2.29 (2H, m), 3.05 (2H, t, J=6.0 Hz),3.53-3.56 (2H, m), 7.48 (1H, t, J=7.6 Hz), 7.86-7.90 (2H, m), 7.96-8.04(3H, m), 8.10 (1H, d, J=2.4 Hz), 8.75 (1H, d, J=2.4 Hz), 11.24 (1H, s).

SYNTHETIC EXAMPLE 51bN-(8-Bromoquinoline-3-yl)-4-(3-methylsulfonylpropyl)benzenesulfonamide

62 mg of the title compound was obtained using 33 mg (0.14 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 66 mg (0.22 mmol)of 4-(3-methylsulfonylpropyl)benzenesulfonyl chloride in the same manneras in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 1.90-1.98 (2H, m), 2.72 (2H, t, J=8.0 Hz), 2.93(3H, s), 3.06 (2H, t, J=8.0 Hz), 7.42 (2H, d, J=8.0 Hz), 7.46 (1H, d,J=7.6 Hz), 7.97 (2H, d, J=7.6 Hz), 8.00 (1H, d, J=7.6 Hz), 8.05 (1H, d,J=2.4 Hz), 8.72 (1H, d, J=2.4 Hz), 11.01 (1H, s).

SYNTHETIC EXAMPLE 52bN-(8-Bromoquinoline-3-yl)-4-fluorobenzenesulfonamide

50 mg of the title compound was obtained using 33 mg (0.14 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 39 mg (0.20 mmol)of 4-fluorobenzenesulfonyl chloride in the same manner as in SyntheticExample 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.40 (1H, t, J=8.8 Hz), 7.47 (1H, t, J=7.6 Hz),7.89-7.93 (2H, m), 9.78 (1H, dd, J=0.9, 7.6 Hz), 8.01 (1H, dd, J=0.9,7.6 Hz), 8.06 (1H, d, J=2.4 Hz), 8.71 (1H, d, J=2.4 Hz), 11.06 (1H, s).

SYNTHETIC EXAMPLE 53bN-(8-Bromoquinoline-3-yl)-4-methoxy-2-pyridazinesulfonamide

Under ice-cooling, chlorine gas was brown into a concentratedhydrochloric acid solution (8 ml) containing 0.86 g (3.7 mmol,Production Example 14b) of 2-benzylthio-5-methoxypyridazine for onehour, followed by stirring. Then, ice-water was added to the reactionsolution, followed by extracting with ethyl acetate. The organic layerwas successively washed with water and brine, dried over magnesiumsulfate and concentrated, to give 700 mg (2.1 mmol) of the residue. 93mg of the title compound was obtained using 180 mg (0.54 mmol) of theresidue and 60 mg (0.27 mmol, Production Example 5b) of3-amino-8-bromoquinoline in the same manner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 4.07 (3H, s), 7.44 (1H, d, J=9.2 Hz), 7.47 (1H,t, J=7.6 Hz), 7.96 (1H, t, J=7.6 Hz), 8.02 (1H, t, J=7.6 Hz), 8.13 (1H,d, J=2.4 Hz), 8.17 (1H, d, J=9.2 Hz), 8.82 (1H, d, J=2.4 Hz), 11.54 (1H,s).

SYNTHETIC EXAMPLE 54b N-(8-Bromoquinoline-3-yl)-benzenesulfonamide

49 mg of the title compound was obtained using 30 mg (0.13 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 35 mg (0.20 mmol)of benzenesulfonyl chloride in the same manner as in Synthetic Example1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.45 (1H, d, J=7.6 Hz), 7.53-7.63 (3H, m),7.84-7.86 (2H, m), 7.96 (1H, dd, J=1.2, 7.6 Hz), 7.99 (1H, dd, J=1.2,7.6 Hz), 8.04 (1H, d, J=2.8 Hz), 8.71 (1H, d, J=2.8 Hz), 11.02 (1H, s).

SYNTHETIC EXAMPLE 55bN-(8-Bromoquinoline-3-yl)-4-carboxyamido-2-pyridinesulfonamide

Chlorine gas was brown into a concentrated hydrochloric acid solution(16 ml) containing 1.1 g (4.3 mmol, Production Example 15b) of2-benzylthio-4-carboxyamidopyridine for one hour under ice-cooling,followed by stirring. Then, the reaction solution was added toice-water, followed by extracting with ethyl acetate. The organic layerwas successively washed with water and brine, dried over magnesiumsulfate and concentrated.

37 mg of the title compound was obtained using 140 mg (0.40 mmol) of theresidue and 45 mg (0.20 mmol) of 3-amino-8-bromoquinoline in the samemanner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.46 (1H, d, J=8.0 Hz), 7.94-7.96 (2H, m),8.00-8.02 (2H, m), 8.12 (1H, d, J=2.4 Hz), 8.44 (1H, br), 8.49 (1H, br),8.83-8.85 (2H, m), 11.35 (1H, s)

SYNTHETIC EXAMPLE 56bN-(8-Bromoquinoline-3-yl)-3-methoxybenzenesulfonamide

70 mg of the title compound was obtained using 40 mg (0.18 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 56 mg (0.27 mmol)of 3-methoxybenzenesulfonyl chloride in the same manner as in SyntheticExample 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 3.76 (3H, s), 7.17 (1H, dd, J=2.8, 8.0 Hz),7.34-7.40 (2H, m), 7.45 (1H, t, J=7.6 Hz), 7.46 (1H, t, J=7.6 Hz), 7.99(2H, t, J=7.6 Hz), 8.07 (1H, d, J=2.4 Hz), 8.72 (2H, m), 11.35 (1H, d,J=2.4 Hz)

SYNTHETIC EXAMPLE 57bN-(8-Bromoquinoline-3-yl)-3-hydroxybenzenesulfonamide

73 mg of the title compound was obtained using 45 mg (0.20 mmol,Production Example 5b) of 3-amino-8-bromoquinoline and 117 mg (0.61mmol) of 3-hydroxybenzenesulfonyl chloride in the same manner as inSynthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 6.97 (1H, d, J=8.0 Hz), 7.18 (1H, br), 7.25(1H, d, J=8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.47 (1H, t, J=8.0 Hz), 7.97(1H, d, J=8.0 Hz), 8.01 (1H, d, J=8.0 Hz), 8.04 (1H, d, J=2.4 Hz), 8.73(1H, d, J=2.4 Hz), 10.15 (1H, s), 10.96 (1H, s).

SYNTHETIC EXAMPLE 58bN-(4-Bromoquinoline-7-yl)-4-chlorobenzenesulfonamide

20 mg (0.09 mmol, Production Example 20b) of 7-amino-4-bromoisoquinolinewas dissolved in 1.5 ml of pyridine, to which was then added 23 mg of4-chlorobenzenesulfonyl chloride, followed by stirring at roomtemperature overnight. Water was added to the reaction solution, and themixture was extracted with ethyl acetate. The extract was dried overmagnesium sulfate and concentrated. Then, the resulting residue waspurified by silica gel thin layer chromatography, to give 13 mg of thetitle compound.

Melting point: gradually decomposed from 229° C.

¹H-NMR (DMSO-d₆) δ(ppm): 7.59-7.61 (2H, m), 7.66 (1H, dd, J=2 Hz, 9.2Hz), 7.82-7.84 (3H, m), 7.99 (1H, d, J=9.2 Hz), 8.60 (1H, s).

SYNTHETIC EXAMPLE 59bN-(4-Bromoisoquinoline-7-yl)-6-chloro-3-pyridinesulfonamide

The title compound was obtained using 7-amino-4-isoquinoline (ProductionExample 20b) and 6-chloro-3-pyridinesulfonyl chloride in the same manneras in Synthetic Example 57b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.66 (1H, dd, J=2.4 Hz, 9.2 Hz), 7.70 (1H, d,J=8.4 Hz), 7.89 (1H, d, J=2.4 Hz), 8.02 (1H, d, J=9.2 Hz), 8.20 (1H, dd,J=2.4 Hz, 8.4 Hz), 8.64 (1H, s), 8.84 (1H, d, J=2.4 Hz), 9.26 (1H, s).

SYNTHETIC EXAMPLE 60b 2-(4-Chlorobenzenesulfonylamino)-1,6-naphthyridine

2-Amino-1,6-naphthyridine (200 mg, Production Example 25b) was dissolvedin dichloromethane (6.0 ml), to which were then added triethylamine(0.20 ml) and 4-chlorobenzenesulfonyl chloride (0.31 g), followed bystirring at 40° C. for 1.5 hours. An aqueous saturated sodiumbicarbonate was added thereto, followed by extracting with ethylacetate. The extract was washed with brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column, to give the title compound (84 mg,21.44%) as pale yellow crystals.

¹H-NMR (CDCl₃) δ(ppm): 7.10 (1H, d, J=9.2 Hz), 7.37 (1H, d, J=5.4 Hz),7.46 (2H, d, J=8.8 Hz), 7.93 (2H, d, J=8.8 Hz), 8.94 (1H, d, J=9.2 Hz),8.66 (1H, d, J=5.4 Hz), 8.92 (1H, br s).

SYNTHETIC EXAMPLE 61b1-Chloro-6-(4-cyanobenzenesulfonylamino)isoquinoline

The title compound was obtained using 6-amino-1-chloro-isoquinoline(Production Example 23b) and 4-cyanobenzenesulfonyl chloride in the samemethod as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 7.52 (1H, dd, J=2.0, 8.8 Hz), 7.68 (1H, d,J=2.0 Hz), 7.79 (1H, d, J=5.6 Hz), 8.03 (4H, m), 8.18 (1H, d, J=5.6 Hz),8.21 (1H, d, J=8.8 Hz), 11.36 (1H, s).

SYNTHETIC EXAMPLE 62b1-Chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline

The title compound was obtained using 6-amino-1-chloro-isoquinoline(Production Example 23b) and 4-chlorobenzenesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 7.33 (1H, br s), 7.39 (1H, dd, J=2.0, 8.8 Hz),7.44 (2H, d, J=8.8 Hz), 7.50 (1H, d, J=5.6 Hz), 7.58 (1H, d, J=2.0 Hz),7.81 (2H, d, J=8.8 Hz), 8.24 (1H, d, J=5.6 Hz), 8.25 (1H, d, J=8.8 Hz).

FAB-MS: 353.

SYNTHETIC EXAMPLE 63b1-Chloro-6-(4-pyrrolidine-1-ylsulfonyl)benzenesulfonylamino)isoquinoline

The target compound was obtained using 6-amino-1-chloro-isoquinoline(Production Example 23b) and 4-(pyrrolidine-1-ylsulfonyl)benzenesulfonylchloride in the same method as in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 1.71 (4H, m), 3.20 (4H, t, J=7.0 Hz), 7.46 (1H,d, J=5.4 Hz), 7.49 (1H, dd, J=2.0, 9.2 Hz), 7.61 (1H, d, J=2.0 Hz), 7.87(2H, d, J=8.8 Hz), 8.02 (2H, d, J=8.8 Hz), 8.19 (1H, d, J=9.2 Hz), 8.20(1H, d, J=5.4 Hz), 9.72 (1H, s).

SYNTHETIC EXAMPLE 64b1-Chloro-6-(4-(N-ethylsulfamoyl)benzenesulfonylamino)isoquinoline

The title compound was obtained using 6-amino-1-chloro-isoquinoline(Production Example 23b) and 4-(N-ethylsulfamoyl)benzenesulfonylchloride in the same method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 0.81 (3H, t, J=7.2 Hz), 2.73 (2H, m), 7.53 (1H,d, J=9.2 Hz), 7.67 (1H, s), 7.75 (1H, d, J=6.0 Hz), 7.78 (1H, d, J=6.0Hz), 7.92 (2H, d, J=8.0 Hz).

SYNTHETIC EXAMPLE 65b1-Methoxy-6-(pyridine-3-ylsulfonylamino)isoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 3-pyridinesulfonyl chloride in the samemethod as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 4.09 (3H, s), 7.09 (1H, d, J=6.0 Hz), 7.25 (1H,dd, J=2.0, 8.8 Hz), 7.37 (1H, d, J=8.0, 8.8 Hz), 7.48 (1H, d, J=2.0 Hz),7.96 (1H, d, J=6.0 Hz), 8.07 (1H, ddd, J=1.6, 2.0, 8.0 Hz), 8.14 (1H, d,J=8.8 Hz), 8.74 (1H, dd, J=1.6, 8.8 Hz), 9.08 (1H, d, J=2.0 Hz).

ESI-MS: 316.0.

SYNTHETIC EXAMPLE 66b6-(4-Cyanobenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 4-cyanobenzenesulfonyl chloride in the samemethod as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 3.97 (3H, s), 7.25 (1H, d, J=5.6 Hz), 7.32 (1H,d, J=8.8 Hz), 7.51 (1H, s), 7.90 (1H, d, J=5.6 Hz), 7.97 (2H, d, J=7.6Hz), 8.01 (2H, d, J=7.6 Hz), 8.03 (1H, d, J=8.8 Hz).

SYNTHETIC EXAMPLE 67b6-(4-Carbamoylbenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained using6-(4-cyanobenzenesulfonylamino)-1-methoxyisoquinoline (ProductionExample 65b) according to the method described in Synthesis, 949 (1989).

¹H-NMR (DMSO-d₆) δ(ppm): 3.96 (3H, s), 7.24 (1H, d, J=6.4 Hz), 7.33 (1H,d, J=9.2 Hz), 7.51 (1H, s), 7.55 (1H, br s), 7.88 (1H, d, J=6.4 Hz),7.89 (2H, d, J=8.0 Hz), 7.93 (2H, d, J=8.0 Hz), 8.01 (1H, d, J=9.2 Hz),8.06 (1H, br s), 10.95 (1H, s).

FAB-MS: 358.

SYNTHETIC EXAMPLE 68b6-(4-(N-Ethylsulfamoyl)benzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 4-(N-ethylsulfamoyl)benzenesulfonylchloride in the same method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 0.81 (3H, t, J=6.8 Hz), 2.71 (2H, m), 3.96 (3H,s), 7.23 (1H, d, J=6.4 Hz), 7.32 (1H, d, J=8.8 Hz), 7.48 (1H, s), 7.73(1H, br s), 7.89 (2H, d, J=8.0 Hz), 7.90 (1H, d, J=6.4 Hz), 8.01 (3H,m), 11.03 (1H, br s).

ESI MS: 422.0.

SYNTHETIC EXAMPLE 69b6-(2-Aminopyridine-5-ylsulfonylamino)-1-methoxyisoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 6-amino-3-pyridinesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 3.96 (3H, s), 6.39 (1H, d, J=8.8 Hz), 6.89 (2H,s), 7.25 (1H, d, J=4.2 Hz), 7.32 (1H, d, J=9.2 Hz), 7.47 (1H, s), 7.64(1H, d, J=9.2 Hz), 7.89 (1H, d, J=4.2 Hz), 8.01 (1H, d, J=8.8 Hz), 8.31(1H, s), 10.95 (1H, s).

ESI MS: 331.0.

SYNTHETIC EXAMPLE 70b1-Methoxy-6-(4-methylbenzenesulfonylamino)isoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 4-toluenesulfonyl chloride in the samemethod as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.28 (3H, s), 3.96 (3H, s), 7.22 (1H, d, J=6.0Hz), 7.32 (3H, m), 7.48 (1H, s), 7.71 (2H, d, J=8.4 Hz), 7.88 (1H, d,J=6.0 Hz), 8.00 (1H, d, J=9.2 Hz), 10.79 (1H, s).

ESI MS: 329.0.

SYNTHETIC EXAMPLE 71b6-(4-Acetylaminobenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 4-acetamidobenzenesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.01 (3H, s), 3.96 (3H, s), 7.23 (1H, d, J=6.0Hz), 7.32 (1H, d, J=9.2 Hz), 7.47 (1H, s), 7.67 (2H, d, J=8.8 Hz), 7.76(2H, d, J=8.8 Hz). 7.88 (1H, d, J=6.0 Hz), 8.00 (1H, d, J=9.2 Hz), 10.26(1H, s), 10.75 (1H, s).

ESI MS: 372.1.

SYNTHETIC EXAMPLE 72b6-(4-Methanesulfonylaminobenzenesulfonylamino)-1-methoxyisoquinoline

The compound synthesized using 6-amino-1-methoxyisoquinoline (ProductionExample 43b) and 4-nitrobenzenesulfonyl chloride in the same manner asin Synthetic Example 1b was processed in the same manner as inProduction Example 170b, to reduce the nitro group thereof. Theresulting compound was dissolved in pyridine and methanesulfonylchloride was added thereto under ice-cooling, followed by stirring for 4hours as it was. Brine was added thereto, followed by extracting withethyl acetate. The extract was washed with brine and dried overanhydrous magnesium sulfate. After evaporating the solvent, the residuewas purified by silica gel column and the resulting crystals wererecrystallized from ethanol, to give the title compound.

¹H-NMR (DMSO-d₆) δ(ppm): 3.06 (3H, s), 3.97 (3H, s), 7.24 (3H, m), 7.33(1H, d, J=9.0 Hz), 7.49 (1H, s), 7.79 (2H, d, J=8.8 Hz), 7.89 (1H, d,J=6.0 Hz), 8.01 (1H, d, J=9.0 Hz), 10.39 (1H, s), 10.80 (1H, s).

ESI MS: 372.1.

SYNTHETIC EXAMPLE 73b6-(2-Chloropyridine-5-ylsulfonylamino)-1-methoxyisoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 6-chloro-3-pyridinesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 3.31 (3H, s), 3.99 (3H, s), 7.30 (1H, d, J=6.0Hz), 7.34 (1H, d, J=8.8 Hz), 7.56 (1H, s), 7.71 (1H, d, J=8.8 Hz), 7.92(1H, d, J=6.0 Hz), 8.06 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 11.13(1H, s).

ESI MS: 350.1.

SYNTHETIC EXAMPLE 74b1-Methoxy-6-(3-methylbenzenesulfonylamino)isoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 3-toluenesulfonyl chloride in the samemethod as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.31 (3H, s), 3.96 (3H, s), 7.22 (1H, d, J=6.0Hz), 7.32 (1H, dd, J=2.0, 8.8 Hz), 7.39 (2H, m), 7.47 (1H, d, J=2.0 Hz),7.62 (1H, m), 7.67 (1H, s), 7.87 (1H, d, J=6.0 Hz), 8.00 (1H, d, J=8.8Hz), 10.84 (1H, s).

SYNTHETIC EXAMPLE 75b 6-Benzylsulfonylamino-1-methoxyisoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and benzylsulfonyl chloride in the same methodas in Synthetic Example 1b.

¹H-NMR (CDCl₃) δ(ppm): 4.13 (3H, s), 4.42 (2H, s), 6.69 (1H, br s), 7.13(2H, m), 7.22 (2H, m), 7.30-7.37 (3H, m), 7.50 (1H, d, J=2.4 Hz), 7.99(1H, d, J=6.0 Hz), 8.20 (1H, d, J=8.8 Hz).

SYNTHETIC EXAMPLE 76b6-(3-Cyanobenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 3-cyanobenzenesulfonyl chloride in the samemethod as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 3.98 (3H, s), 7.28 (1H, d, J=6.0 Hz), 7.34 (1H,dd, J=2.0, 8.8 Hz), 7.53 (1H, d, J=2.0 Hz), 7.75 (1H, dd, J=8.0, 8.0Hz), 7.91 (1H, d, J=6.0 Hz), 8.04 (1H, d, J=8.8 Hz), 8.09 (2H, m), 9.29(1H, m), 11.05 (1H, s).

SYNTHETIC EXAMPLE 77b1-Methoxy-6-(4-thiazole-2-ylbenzenesulfonylamino)isoquinoline

The compound (40 mg) obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 4-iodobenzenesulfonyl chloride in the samemethod as in Synthetic Example 1b, 2-tri-n-butylstannylthiazole (136 mg)and tetrakis(triphenylphosphine)palladium (0) (11 mg) were heated underreflux for one hour in toluene in a nitrogen atmosphere. Afterevaporating the solvent, the residue was purified by silica gel column.The resulting crystals were recrystallized from methanol, to give thetitle compound (20 mg).

¹H-NMR (CDCl₃) δ(ppm): 4.08 (3H, s), 6.94 (1H, br s), 7.09 (1H, d, J=6.0Hz), 7.23 (1H, dd, J=2.0, 8.8 Hz), 7.41 (1H, d, J=3.6 Hz), 7.45 (1H, d,J=2.0 Hz), 7.89 (2H, d, J=8.4 Hz), 7.90 (1H, d, J=8.6 Hz), 7.95 (1H, d,J=6.0 Hz), 7 82 (2H, d, J=8.4 Hz), 8.13 (1H, d, J=8.8 Hz).

SYNTHETIC EXAMPLE 78b6-(4-Chlorobenzenesulfonylamino)-1-methoxyisoquinoline

The title compound was obtained using 6-amino-1-methoxyisoquinoline(Production Example 43b) and 4-chlorobenzenesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 4.00 (3H, s), 7.27 (1H, d, J=5.6 Hz), 7.45 (1H,dd, J=2.0, 8.8 Hz), 7.53 (1H, d, J=2.0 Hz), 7.63 (2H, d, J=8.8 Hz), 7.85(1H, d, J=8.8 Hz), 7.92 (1H, d, J=5.6 Hz), 8.06, (1H, J=8.8 Hz), 10.97(1H, s).

SYNTHETIC EXAMPLE 79b6-(4-Chlorobenzenesulfonylamino)-1-methylisoquinoline

The title compound was obtained using 6-amino-1-methylisoquinoline(Production Example 33b) and 4-chlorobenzenesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.76 (3H, s), 7.56 (1H, d, J=6.0 Hz), 7.52 (2H,m), 7.60 (2H, d, J=8.8 Hz), 7.82 (2H, d, J=8.8 Hz), 8.08 (1H, d, J=9.2Hz), 8.20 (1H, d, J=6.0 Hz).

ESI-MS: 333.0.

SYNTHETIC EXAMPLE 80b6-(4-Chlorobenzenesulfonylamino)-1-ethylisoquinoline

The title compound was obtained using 6-amino-1-ethylisoquinoline(Production Example 48b) and 4-chlorobenzenesulfonyl chloride in thesame manner as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 1.39 (3H, t, J=7.6 Hz), 3.25 (2H, q, J=7.6 Hz),7.35 (1H, dd, J=2.4, 9.2 Hz), 7.38 (1H, d, J=5.6 Hz), 7.41 (2H, d, J=8.8Hz), 7.53 (1H, d, J=2.4 Hz), 7.81 (2H, d, J=8.8 Hz), 8.05 (1H, d, J=9.2Hz), 8.37 (1H, d, J=5.6 Hz).

ESI-MS: 347.0.

SYNTHETIC EXAMPLE 81b6-(4-Chlorobenzenesulfonylamino)-4-ethylisoquinoline

The title compound was obtained using 6-amino-4-ethylisoquinoline(Production Example 66b) and 4-chlorobenzenesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 1.18 (3H, t, J=7.2 Hz), 2.85 (2H, q, J=7.2 Hz),7.38 (1H, d, J=8.8 Hz), 7.60 (1H, s), 7.62 (2H, d, J=8.0 Hz), 7.82 (2H,d, J=8.0 Hz), 8.00 (1H, d, J=8.8 Hz), 8.26 (1H, s), 8.99 (1H, s).

SYNTHETIC EXAMPLE 82b6-(4-Chlorobenzenesulfonylamino)-4-methylisoquinoline

The title compound was obtained using 6-amino-4-methylisoquinoline(Production Example 58b) and 4-chlorobenzenesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.43 (3H, s), 7.41 (1H, d, J=8.8 Hz), 7.56 (1H,s), 7.62 (2H, d, J=8.8 Hz), 7.85 (2H, d, J=8.8 Hz), 7.99 (1H, d, J=8.8Hz), 8.26 (1H, s), 8.98 (1H, s), 11.09 (1H, br s).

SYNTHETIC EXAMPLE 83b6-(4-Chlorobenzenesulfonylamino)-3-methylisoquinoline

The title compound was obtained using 6-amino-3-methylisoquinolinne(Production Example 76b) and 4-chlorobenzenesulfonyl chloride in thesame method as in Synthetic Example 1b.

¹H-NMR (DMSO-d₆) δ(ppm): 2.53 (3H, s), 7.30 (1H, d, J=8.8 Hz), 7.45 (1H,s), 7.50 (1H, s), 7.62 (2H, d, J=8.4 Hz), 7.84 (2H, d, J=8.4 Hz), 7.93(1H, d, J=8.8 Hz), 9.03 (1H, s).

SYNTHETIC EXAMPLE 84b6-(4-Chlorobenzenesulfonylamino)-1-cyanoisoquinoline

The compound obtained using 6-aminoisoquinoline (0.5 g, Synthesis, 733(1975)) and 4-chlorobenzenesulfonyl chloride (0.88 g) in the same methodas in Synthetic Example 1b was dissolved in chloroform (150 ml). Underice-cooling, m-chloroperbenzoic acid (0.9 g) was added thereto, followedby stirring at room temperature overnight. The solvent was evaporated,and the resulting crystals were washed with diethyl ether, collected byfiltration and dried, to give6-(4-chlorobenzenesulfonylamino)isoquinoline-N-oxide (1.072 g). Inacetonitrile (1.5 ml) was dissolved 50 mg in the amount of the product,to which were then added trimethyl cyanide (0.08 ml) and triethylamine(0.04 ml), followed by heating under reflux for 3.5 hours. Afterevaporating the solvent, the residue was purified by silica gel column,to give the title compound (23 mg, 64%) as yellow crystals.

¹H-NMR (DMSO-d₆) δ(ppm): 7.66 (2H, d, J=8.8 Hz), 7.67 (1H, dd, J=2.0,9.2 Hz), 7.80 (1H, d, J=2.0 Hz), 7.93 (2H, d, J=8.8 Hz), 8.17 (1H, d,J=9.2 Hz), 8.18 (1H, d, J=5.6 Hz), 8.59 (1H, d, J=5.6 Hz).

ESI-MS: 344.1

SYNTHETIC EXAMPLE 85b1-Carbamoyl-6-(4-chlorobenzenesulfonylamino)isoquinoline

Crystals obtained from6-(4-chlorobenzenesulfonylamino)-1-cyanoisoquinoline (30 mg, SyntheticExample 83b) according to the method described in Synthesis, 949 (1989)were washed with diethyl ether, to give the title compound (26 mg, 82%)as colorless crystals.

¹H-NMR (CDCl₃) δ(ppm): 6.25 (1H, br s), 7.35 (2H, d, J=8.8 Hz), 7.43(1H, dd, J=2.0, 9.2 Hz), 7.62 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=6.8 Hz),7.81 (2H, d, J=8.8 Hz), 8.04 (1H, br s), 8.37 (1H, br s), 9.32 (1H, d,J=9.2 Hz), 9.76 (1H, br s).

SYNTHETIC EXAMPLE 86b6-(4-Chlorobenzenesulfonylamino)-1-methylaminoisoquinoline

1-Chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (50 mg, SyntheticExample 61b) and a 40% methylamine methanol solution (5.0 ml) wereheated at 130° C. in a sealed tube for 18 hours. After cooling as itwas, an aqueous saturated sodium bicarbonate was added thereto, and themixture was extracted with ethyl acetate. The extract was washed withbrine and dried over anhydrous magnesium sulfate. After evaporating thesolvent, the residue was purified by silica gel column, to give thetitle compound (28 mg, 52%) as a pale yellow solid.

¹H-NMR (CDCl₃) δ(ppm): 3.14 (3H, s), 5.22 (1H, br s), 6.89 (1H, d, J=6.0Hz), 7.19 (1H, dd, J=2.4 Hz, 9.2 Hz), 7.31 (1H, d, J=2.4 Hz), 7.40 (2H,d, J=8.8 Hz), 7.64 (1H, d, J=9.2 Hz), 7.73 (2H, d, J=8.8 Hz), 7.98 (1H,d, J=6.0 Hz).

SYNTHETIC EXAMPLE 87b1-Amino-6-(4-chlorobenzenesulfonylamino)isoquinoline

Crystals obtained using6-(4-chlorobenzenesulfonylamino)isoquinoline-N-oxide (intermediate inSynthetic Example 83b, 50 mg) according to the method described in J.Medicine 84,35 (1964) were washed with diethyl ether and dried, to givethe title compound (2 mg) as pale brownish crystals.

¹H-NMR (DMSO-d₆) δ(ppm): 7.76 (1H, d, J=6.0 Hz), 6.93 (2H, br s), 7.15(1H, dd, J=2.0, 8.8 Hz), 7.27 (1H, d, J=2.0 Hz), 7.59 (2H, d, J=8.8 Hz),7.63 (1H, d, J=6.0 Hz), 7.80 (2H, d, J=8.8 Hz), 9.05 (1H, d, J=6.0 Hz).

ESI-MS: 334.1.

SYNTHETIC EXAMPLE 88b6-(4-Chlorobenzenesulfonylamino)-1-dimethylaminoisoquinoline

1-Chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Synthetic Example61b, 60 mg) was dissolved in dimethyl sulfoxide (1 ml), to which wasthen added a 50% dimethylamine methanol solution (0.04 ml), followed byheating under stirring at 80° C. for 10 hours. After cooling as it was,water was added thereto, followed by extracting with ethyl acetate. Theextract was washed with brine and dried over anhydrous magnesiumsulfate. After evaporating the solvent, the residue was purified bypreparative TLC and solidified using isopropyl ether, to give the titlecompound (17 mg).

¹H-NMR (DMSO-d₆) δ(ppm): 2.96 (6H, s), 7.12 (1H, d, J=6.0 Hz), 7.27 (1H,dd, J=2.0, 9.2 Hz), 7.45 (1H, d, J=2.0 Hz), 7.64 (2H, d, J=8.8 Hz), 7.85(2H, d, J=8.8 Hz), 7.93 (1H, d, J=6.0 Hz), 8.01 (1H, d, J=9.2 Hz), 10.91(1H, br s).

SYNTHETIC EXAMPLE 89b6-(4-Chlorobenzenesulfonylamino)-1-hydroxyisoquinoline

6-(4-Chlorobenzenesulfonylamino)isoquinoline-N-oxide (intermediate inSynthetic Example 83b, 50 mg) was dissolved in acetic acid anhydride(0.75 ml), followed by heating under stirring at 80° C. for 16 hours.Then, the mixture was refluxed under heating for 2 hours. After coolingas it was, an aqueous saturated sodium bicarbonate was added thereto,followed by extracting with ethyl acetate. The extract was washed withbrine and dried over anhydrous magnesium sulfate. After evaporating thesolvent, the residue was dissolved in ethanol (2.0 ml) and water (0.5ml), followed by heating under reflux for 0.5 hours. After evaporatingthe solvent, the residue was purified by silica gel column, to give thetitle compound (20 mg) as a pale red solid.

¹H-NMR (CDCl₃) δ(ppm): 6.58 (1H, d, J=7.2 Hz), 7.22 (1H, d, J=7.2 Hz),7.31 (1H, dd, J=2.0, 8.4 Hz), 7.54 (1H, d, J=2.0 Hz), 7.56 (2H, d, J=8.8Hz), 8.01 (2H, d, J=8.8 Hz), 8.53 (1H, d, J=8.4 Hz), 10.36 (1H, br s).

ESI-MS: 335.1.

SYNTHETIC EXAMPLE 90b6-(4-Chlorobenzenesulfonylamino)-1-ethoxyisoquinoline

1-Chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Synthetic Example61b, 57 mg) was dissolved in dimethyl sulfoxide (1 ml). Ethanol (0.1 ml)and 60% sodium hydride (14 mg) were added thereto, followed by heatingunder stirring at 80° C. for 9 hours. After cooling as it was, water wasadded thereto, followed by extracting with ethyl acetate. The extractwas washed with brine and dried over anhydrous magnesium sulfate. Afterevaporating the solvent, the residue was purified by preparative TLC andsolidified using isopropyl ether, to give the title compound (21 mg).

¹H-NMR (DMSO-d₆) δ(ppm): 1.38 (3H, t, J=7.2 Hz), 4.46 (2H, q, J=7.2 Hz),7.24 (1H, d, J=6.0 Hz), 7.35 (1H, dd, J=2.0, 9.2 Hz), 7.50 (1H, d, J=2.0Hz), 7.63 (2H, d, J=8.8 Hz), 7.90 (1H, d, J=6.0 Hz), 8.04 (1H, d, J=9.2Hz), 10.94 (1H, br s).

SYNTHETIC EXAMPLE 91b N-(5-Vinylquinoline-2-yl)-3-pyridinesulfonamide

A solution containing 2-amino-5-bromoquinoline (510 mg, ProductionExample 1b), vinyltributyltin (0.94 ml), toluene (4 ml),tetrakistriphenylphosphinepalladium (0 valence) (20 mg) and2,6-ditertiarybutyl/p-cresol (about 0.1 mg) was stirred at 120° C. for 4hours. After the reaction mixture was returned to room temperature,water was added thereto, followed by extracting with ethyl acetate. Theethyl acetate layer was dried over sodium sulfate and concentrated.Then, the resulting solid was washed with hexane, to give 282 mg of asolid including a vinyl material. The solid was dissolved in 2 ml ofpyridine and 412 mg of 3-pyridinesulfonyl chloride was added thereto,followed by stirring at room temperature overnight. Water was addedthereto, followed by extracting with ethyl acetate. The ethyl acetatelayer was dried over sodium sulfate and concentrated. Then, theresulting solid was washed with methanol, to give the title compound(235 mg).

¹H-NMR (CDCl₃) δ(ppm): 5.59 (1H, dd, J=10.8 Hz, 1.5 Hz), 5.82 (1H, dd,J=16.9 Hz, 1.5 Hz), 6.95 (1H, d, J=10.3 Hz), 7.20 (1H, dd, J=10.8 Hz,16.9 Hz), 7.36 (1H, d, J=8.5 Hz), 7.43 (1H, m), 7.50 (1H, d, J=8.5 Hz),7.62 (1H, t, J=8.5 Hz), 8.24 (1H, d, J=10.3 Hz), 8.29 (1H, m), 8.74 (1H,m), 9.22 (1H, m).

SYNTHETIC EXAMPLE 92bN-(4-Trifluoromethylcumarin-7-yl)-4-chlorobenzenesulfonamide

203 mg (0.96 mmol) of 4-chlorobenzenesulfonyl chloride was added to apyridine solution (3 ml) containing 200 mg (0.87 mmol) of7-amino-4-trifluoromethylcumarin and 1 mg of 4-dimethylaminopyridine,followed by stirring at 70° C. for 50 minutes. An aqueous 2 Nhydrochloric acid was added thereto, followed by extracting with ethylacetate. The organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated. The resulting residue was crystallizedfrom ethyl acetate-diisopropyl ether, to give 253 mg of the titlecompound as a pale yellow solid.

¹H-NMR (DMSO-d₆) δ(ppm): 6.87 (1H, s), 7.12 (1H, d, J=2.4 Hz), 7.17 (1H,dd, J=2.6, 8.4 Hz), 7.60 (1H, d, J=8.4 Hz), 7.67 (2H, d, J=6.8 Hz), 7.87(2H, d, J=6.8 Hz), 11.29 (1H, s).

1. A method for treating or improving a disease against which anintegrin expression inhibition is effective, wherein said disease is atleast one selected from the group consisting of osteoporosis andcoagulation, said method comprising: administering a pharmacologicallyeffective amount of an integrin expression inhibitor of a sulfonamidecompound represented by formula (I^(a)), a pharmacologically acceptablesalt thereof or a hydrate thereof, to a patient in need thereof fortreating or improving said disease:

wherein in formula (I^(a)): the A^(a) ring represents a monocyclic orbicyclic aromatic ring optionally having a substituent; the B^(a) ringrepresents an optionally substituted 6-membered cyclic unsaturatedhydrocarbon or unsaturated 6-membered heterocycle containing onenitrogen atom as a heteroatom; the C^(a) ring represents an optionallysubstituted 5-membered heterocycle containing 1 or 2 nitrogen atoms;R^(1a) represents a hydrogen atom or a C₁-C₆ alkyl group; W^(a)represents a single bond or —CH═CH—; Y^(a) represents a carbon atom ornitrogen atom; and Z^(a) represents a nitrogen atom or —N(R^(2a))—,wherein R^(2a) is a hydrogen atom or a lower alkyl group.
 2. The methodof claim 1, wherein the ring of formula (I^(a)) formed by the B^(a) ringand C^(a) ring is a N-substituted indole, quinoline or isoquinoline. 3.The method of claim 1, wherein said sulfonamide compound isN-(3-cyano-4-methyl-1H-indole-7-yl)-3-cyanobenzene-sulfonamide orN-(5-bromo-3-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide. 4.The method of claim 1, wherein said disease is a disease against whichan antiangiogenic effect is effective.
 5. The method of claim 1, whereinsaid sulfonamide compound, pharmacologically acceptable salt thereof orhydrate thereof is selected from the group consisting ofN-(3-cyano-4-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide;N-(3-cyano-4-methyl-1H-indole-7-yl)-6-chloro-3-pyridinesulfonamide;N-(3-bromo-5-methyl-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide;N-(5-bromo-3-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide;N-(3-bromo-5-methyl-1H-indole-7-yl)-3-cyanobenzenesulfonamide;N-(4-bromo-1H-indole-7-yl)-4-cyanobenzenesulfonamide;N-(4-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide;N-(3-bromo-4-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide;N-(3-bromo-5-methyl-1H-indole-7-yl)-5-cyano-2-thiophenesulfonamide; andN-(4-bromo-3-chloro-1H-indole-7-yl)-2-amino-5-pyrimidinesulfonamide. 6.The method of claim 1, wherein said sulfonamide compound,pharmacologically acceptable salt thereof or hydrate thereof is selectedfrom the group consisting ofN-(3-cyano-4-methyl-1H-indole-7-yl)-3-cyanobenzene-sulfonamide,N-(3-cyano-4-methyl-1H-indole-7-yl)-6-chloro-3-pyridinesulfonamide,N-(3-bromo-5-methyl-1H-indole-7-yl)-4-sulfamoylbenzenesulfonamide andN-(5-bromo-3-chloro-1H-indole-7-yl)-6-amino-3-pyridinesulfonamide.